α-Synuclein的自噬性降解途径及可能机制
|
摘要
第一部分突变型α-synuclein的自噬性降解途径及可能机制
目的观察PC12细胞中突变型α-synuclein与自噬之间的关系和可能的降解途径,探讨其在帕金森病发病机制中的作用。
方法采用RT-PCR方法从人胎脑中克隆野生型α-synuclein基因,采取T-A克隆基因并测定其序列,在此基础上利用单核苷酸差异引物定点诱变构建α-synuclein同义突变基因和致病突变A30P的α-synuclein基因并进行测序;对转染了α-synuclein(A30P)的PC12细胞进行药物干预,检测细胞的增殖活性和CAT、SOD的水平,还采用透射电镜观察细胞超微结构改变以及自噬的特征行改变,同时检测α-synuclein、LC3的蛋白的表达。
结果突变型α-synuclein激活了自噬途径,并加剧了MPP~+的毒性作用,对于转染突变型α-synuclein(A30P)的PC12细胞,形态学上明确有自噬现象的发生,自噬确实参与了变异型α-synuclein(A30P)的降解,从分子生物学角度也检测到LC3-Ⅱ在转染突变型α-synuclein(A30P)的PC12细胞中的表达。自噬抑制剂Wortmannin可加剧α-synuclein积聚和导致细胞死亡, LC3-Ⅱ的表达也受到抑制,而自噬诱导剂Rapamycin则可以促进α-synuclein的降解和细胞生长,LC3-Ⅱ的表达显著增强。
结论转染突变型α-synuclein(A30P)的PC12细胞在形态学上明确有自噬现象的发生,在MPP+作用下,突变型α-synuclein的表达水平明显增高,α-synuclein的异常积聚导致PC12细胞的死亡,而促进自噬有助于突变型α-synuclein的降解,对细胞具有保护作用。
第二部分突变型α-synuclein(A30P)在氧化应激状态下的降解途径和可能机制
目的观察突变型α-synuclein(A30P)在氧化应激状态下的降解途径,探讨其在帕金森病发病机制中的作用和可能机制。
方法利用MPP~+对转染了α-synuclein(A30P)的PC12细胞进行干预,模拟在氧化应激状态下的PD细胞模型,在此基础上,分别给予自噬诱导剂—Rapamycin和抑制剂—Wortmannin,检测细胞的增殖活性,还采用透射电镜观察细胞超微结构改变以及自噬的特征行改变,同时检测α-synuclein、LC3蛋白的表达和细胞培养基中CAT、SOD的水平。
结果在氧化应急状态下(MPP~+),突变型α-synuclein的表达明显增加,自噬水平显著减低;细胞超微结构显示:线粒体肿胀、空泡化,嵴少,内质网扩张,细胞核皱缩,染色质有边集,细胞有凋亡的倾向。而联合使用自噬抑制剂-Wortmannin处理过细胞,细胞培养液中CAT和SOD的水平较单独应用MPP~+的细胞有显著降低,细胞增殖活性明显降低,细胞死亡明显增加;α-synuclein的表达明显增加,自噬水平显著减低;细胞超微结构显示:线粒体肿胀,嵴少,内质网扩张,细胞核皱缩,染色质有边集,并可见凋亡小体。相反,联合使用自噬诱导剂-Rapamycin提高了细胞培养液中CAT和SOD水平,促进了细胞的增殖和分化;α-synuclein的表达明显减低,自噬水平显著增高;细胞超微结构显示:胞质中可见多个具有特征性双层膜结构的自噬小体,胞核、线粒体正常。
结论在氧化应激状态下,突变型α-synuclein(A30P)对外源性毒素的敏感性明显增高,α-synuclein聚集更为显著,自噬水平明显减低,从而导致自噬应激;提高自噬水平有助于突变型α-synuclein的降解,对细胞具有保护作用。
第三部分Rapamycin治疗帕金森病小鼠模型的实验研究及可能机制
目的探讨自噬诱导剂—Rapamycin对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病(PD)小鼠模型是否具有治疗作用及可能机制。
方法Rapamycin采用静脉直接给药对MPTP诱导的PD小鼠模型进行治疗,而后采用免疫组织化学及蛋白印迹分析(Western blot)的方法对PD相关标志物酪氨酸羟化酶(TH)以及α-synuclein的可能改变进行检测,并采用高效液相色谱-电化学检测仪(HPLC-ECD)检测纹状体单胺类递质的可能变化;还采用透射电镜观察细胞超微结构改变以及自噬的特征行改变。为进一步研究自噬在异常积聚的α-synuclein降解过程中的作用,我们对其中一个关键的自噬基因-微管相关蛋白轻链3(microtubule-associated protein light chain 3, LC3)进行检测分析。
结果(1)黑质免疫组化染色显示:NS治疗组较正常对照组TH阳性细胞数明显减少(p=0.003), Rapamycin治疗组可逐渐恢复TH阳性细胞损失;(2)纹状体Western blot结果显示:Rapamycin治疗组较NS治疗组TH表达明显增多;Rapamycin治疗组与NS治疗组比较α-synuclein明显下降(p=0.004);Rapamycin治疗组较NS治疗组LC3明显升高(p=0.003)。(3) HPLC-ECD显示DA及其代谢产物DOPAC在NS治疗组明显下降,而其他单胺类递质则无明显改变;治疗组DOPAC含量较NS治疗组明显升高(p=0.001),与正常对照组无明显差异。(4) NS治疗组较正常对照组DAT和VMAT-2表达明显减少,而Rapamycin治疗组较NS治疗组DAT和VMAT-2表达明显增多,但是通过对比,我们可以发现:Rapamycin治疗组较NS治疗组DAT和VMAT-2升高的程度有明显的差异,与正常对照组比较,Rapamycin治疗组DAT的表达仍低于对照组,而VMAT-2表达却明显高于对照组。DAT和VMAT-2对MPTP的敏感性不同,在经过MPTP后,二者对Rapamycin的反应也存在明显的差异。
结论静脉注射Rapamycin可以对MPTP诱导的小鼠PD模型产生明显的治疗作用; Rapamycin不但可以减少DA能神经元死亡,还能够恢复DA能神经元的功能,从而增加了DOPAC的含量;Rapamycin的治疗作用可能与促进异常积聚的蛋白α-synuclein的降解有关。
Part I Autophagic pathway and probable mechanism in the degradation of mutantα-synuclein in PC12 cells
OBJECTIVE: The accumulation of mutantα-synuclein plays a major role and morphologic evidence of autophagy has been reported in Parkinson disease. We aim to observe the effect of mutantα-synuclein (A30P) in autophagic programmed cell death by transfected PC12 cells and explored its probable role and pathway in PD.
METHODS: We constructed definite PC12 cells which were transfected mutantα-synuclein (A30P) at first and administrate MPP+, Rapamycin and Wortmanin to transfected PC12 cells with mutantα-synuclein. We not only detected proliferative activity of cells with MTT method but also observed the ultrastructure changes of cells and expression ofα-synuclein in different circumstance by Transmission electron microscopy (TEM), Western Blotting and and the level of SOD.
RESULTS: Mutantα-synuclein (A30P) leading to PC12 cells death involvesα-synuclein accumulation, membrane lipid oxidation, and loss of plasma membrane integrity. Mutantα-synuclein (A30P) mediates the toxicity of MPP+. Rapamycin, an inducer of autophagy, reduces the aggregation ofα-synuclein in transfected cells. Meanwhile, Wortmanin, an inhibitor of autophagy, promotes the aggregation ofα-synuclein in transfected cells and induces cells to die.
CONCLUSION: The abnormal aggregation ofα-synuclein induces autophagic programmed cell death in PC12 cells and mutantα-synuclein (A30P) mediates the toxicity of MPP~+. Meanwhile, Rapamycin may reduce the aggregation ofα-synuclein in transfected cells by activation of autophagic pathway.
Part II Mutant -synuclein (A30P)are degraded by autophagic pathway and mechanism under oxidative stress
Objective The accumulation of mutantα-synuclein plays a major role and morphologic evidence of autophagy has been reported in Parkinson disease. We aim to observe the effect of MPP~+ to mutantα-synuclein (A30P) in autophagic programmed cell death by transfected PC12 cells and explored its probable role and degradative pathway in PD. Method We constructed definite PC12 cells which were transfected mutantα-synuclein (A30P) at first and administrate MPP~+ to establish the the model of PD with cells under oxidative stress. Rapamycin and Wortmanin were administered to transfected PC12 cells with mutantα-synuclein respectively . We not only detected proliferative activity of cells with MTT method but also observed the ultrastructure changes of cells by Transmission electron microscopy (TEM). Meanwhile expression ofα-synuclein and LC3 in different circumstance was examined by Western Blotting. Moreover, the levels of CAT and SOD in cell cultures were also compared in order to discuss the relation between oxidative stress and autophagy. Results MPP~+ to mutantα-synuclein (A30P) leads to PC12 cells death by means of autophagy involvesα-synuclein accumulation, membrane lipid oxidation, and loss of plasma membrane integrity. Mutantα-synuclein (A30P) mediates the toxicity and enhances the sensitivity of MPP~+ . Rapamycin, an inducer of autophagy, reduces the aggregation ofα-synuclein in transfected cells. Meanwhile, Wortmanin, an inhibitor of autophagy, promotes the aggregation ofα-synuclein in transfected cells and induces cells to die. Conclusion Mutantα-synuclein (A30P) mediates the toxicity of MPP~+. Meanwhile, inducer of autophagy-Rapamycin may reduce the aggregation ofα-synuclein in transfected cells by activation of autophagic pathway.
Part III Therapeutic effect and probable mechanisim of Rapamycin on MPTP-induced parkinsonism in mice
OBJECTIVE: To investigate the effects of inducer of autophagy-Rapamycin on the functional and morphological outcome in a mice model of Parkinson s disease (PD) rendered by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).
BACKGROUND: In neurodegenerative disorders such as PD, autophagy participates in the cell death process of dopaminergic neuron.α-Synuclein is one of the major components of Lewy bodies and Lewy neuritis and mutation ofα-synuclein such as a-synuclein mutants (A53T and A30P) may be involved in the development of familial PD. Our previous study demonstrated that Rapamycin may induce autophagy and decrease aggregation ofα-synuclein and cell death.
METHODS: Male C57BL mice were treated with Rapamycin(3mg/kg) by i.v for 7 days after MPTP administration(30mg/kg.14d), and were compared with saline-treated PD mice and normal control group. Immunohistochemistry and Western blot were used to detect the alterations of PD biomarker including tyrosine hydroxylase (TH), and the level of autophagy was investigated by microtubule-associated protein light chain 3(LC3) andα-synuclein cleavage. In addition, monoamine neurotransmitters in the striatum of mice were measured by the high performance liquid chromatography (HPLC).
RESULTS: TH immunohistochemistry indicated that the number of dopaminergic neurons in the substantia nigra was increased in Rapamycin-treated mice compared with saline-treated mice (p=0.003). Western blot demonstrated the similar TH protein expression in striatum as the number of dopaminergic neurons.α-Synuclein was markedly decreased in Rapamycin-treated mice compared with the NS-treated mice(p=0.004) and LC3 was markedly increased in Rapamycin-treated mice compared with the NS-treated mice(p=0.003). Meanwhile, DAT and VMAT-2 were markedly decreased in Rapamycin-treated and NS-treated mice compared with control group. Although the degree was different, DAT and VMAT-2 were markedly increased in Rapamycin-treated compared with NS-treated mice. The concentrations of striatal dopamine and its metabolite DOPAC compared to the normal mice were decreased significantly in other groups. Rapamycin-treated mice minimized the reduction of DOPAC compared with the NS-treated mice (p=0.001).
CONCLUSIONS: These results showed that Rapamycin is able to rescue the dopaminergic neurons in different doses and reverses the loss of DOPAC through activation of autophagy-lysosome pathway, and it may be a promising therapeutic agent in PD.
目的观察PC12细胞中突变型α-synuclein与自噬之间的关系和可能的降解途径,探讨其在帕金森病发病机制中的作用。
方法采用RT-PCR方法从人胎脑中克隆野生型α-synuclein基因,采取T-A克隆基因并测定其序列,在此基础上利用单核苷酸差异引物定点诱变构建α-synuclein同义突变基因和致病突变A30P的α-synuclein基因并进行测序;对转染了α-synuclein(A30P)的PC12细胞进行药物干预,检测细胞的增殖活性和CAT、SOD的水平,还采用透射电镜观察细胞超微结构改变以及自噬的特征行改变,同时检测α-synuclein、LC3的蛋白的表达。
结果突变型α-synuclein激活了自噬途径,并加剧了MPP~+的毒性作用,对于转染突变型α-synuclein(A30P)的PC12细胞,形态学上明确有自噬现象的发生,自噬确实参与了变异型α-synuclein(A30P)的降解,从分子生物学角度也检测到LC3-Ⅱ在转染突变型α-synuclein(A30P)的PC12细胞中的表达。自噬抑制剂Wortmannin可加剧α-synuclein积聚和导致细胞死亡, LC3-Ⅱ的表达也受到抑制,而自噬诱导剂Rapamycin则可以促进α-synuclein的降解和细胞生长,LC3-Ⅱ的表达显著增强。
结论转染突变型α-synuclein(A30P)的PC12细胞在形态学上明确有自噬现象的发生,在MPP+作用下,突变型α-synuclein的表达水平明显增高,α-synuclein的异常积聚导致PC12细胞的死亡,而促进自噬有助于突变型α-synuclein的降解,对细胞具有保护作用。
第二部分突变型α-synuclein(A30P)在氧化应激状态下的降解途径和可能机制
目的观察突变型α-synuclein(A30P)在氧化应激状态下的降解途径,探讨其在帕金森病发病机制中的作用和可能机制。
方法利用MPP~+对转染了α-synuclein(A30P)的PC12细胞进行干预,模拟在氧化应激状态下的PD细胞模型,在此基础上,分别给予自噬诱导剂—Rapamycin和抑制剂—Wortmannin,检测细胞的增殖活性,还采用透射电镜观察细胞超微结构改变以及自噬的特征行改变,同时检测α-synuclein、LC3蛋白的表达和细胞培养基中CAT、SOD的水平。
结果在氧化应急状态下(MPP~+),突变型α-synuclein的表达明显增加,自噬水平显著减低;细胞超微结构显示:线粒体肿胀、空泡化,嵴少,内质网扩张,细胞核皱缩,染色质有边集,细胞有凋亡的倾向。而联合使用自噬抑制剂-Wortmannin处理过细胞,细胞培养液中CAT和SOD的水平较单独应用MPP~+的细胞有显著降低,细胞增殖活性明显降低,细胞死亡明显增加;α-synuclein的表达明显增加,自噬水平显著减低;细胞超微结构显示:线粒体肿胀,嵴少,内质网扩张,细胞核皱缩,染色质有边集,并可见凋亡小体。相反,联合使用自噬诱导剂-Rapamycin提高了细胞培养液中CAT和SOD水平,促进了细胞的增殖和分化;α-synuclein的表达明显减低,自噬水平显著增高;细胞超微结构显示:胞质中可见多个具有特征性双层膜结构的自噬小体,胞核、线粒体正常。
结论在氧化应激状态下,突变型α-synuclein(A30P)对外源性毒素的敏感性明显增高,α-synuclein聚集更为显著,自噬水平明显减低,从而导致自噬应激;提高自噬水平有助于突变型α-synuclein的降解,对细胞具有保护作用。
第三部分Rapamycin治疗帕金森病小鼠模型的实验研究及可能机制
目的探讨自噬诱导剂—Rapamycin对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病(PD)小鼠模型是否具有治疗作用及可能机制。
方法Rapamycin采用静脉直接给药对MPTP诱导的PD小鼠模型进行治疗,而后采用免疫组织化学及蛋白印迹分析(Western blot)的方法对PD相关标志物酪氨酸羟化酶(TH)以及α-synuclein的可能改变进行检测,并采用高效液相色谱-电化学检测仪(HPLC-ECD)检测纹状体单胺类递质的可能变化;还采用透射电镜观察细胞超微结构改变以及自噬的特征行改变。为进一步研究自噬在异常积聚的α-synuclein降解过程中的作用,我们对其中一个关键的自噬基因-微管相关蛋白轻链3(microtubule-associated protein light chain 3, LC3)进行检测分析。
结果(1)黑质免疫组化染色显示:NS治疗组较正常对照组TH阳性细胞数明显减少(p=0.003), Rapamycin治疗组可逐渐恢复TH阳性细胞损失;(2)纹状体Western blot结果显示:Rapamycin治疗组较NS治疗组TH表达明显增多;Rapamycin治疗组与NS治疗组比较α-synuclein明显下降(p=0.004);Rapamycin治疗组较NS治疗组LC3明显升高(p=0.003)。(3) HPLC-ECD显示DA及其代谢产物DOPAC在NS治疗组明显下降,而其他单胺类递质则无明显改变;治疗组DOPAC含量较NS治疗组明显升高(p=0.001),与正常对照组无明显差异。(4) NS治疗组较正常对照组DAT和VMAT-2表达明显减少,而Rapamycin治疗组较NS治疗组DAT和VMAT-2表达明显增多,但是通过对比,我们可以发现:Rapamycin治疗组较NS治疗组DAT和VMAT-2升高的程度有明显的差异,与正常对照组比较,Rapamycin治疗组DAT的表达仍低于对照组,而VMAT-2表达却明显高于对照组。DAT和VMAT-2对MPTP的敏感性不同,在经过MPTP后,二者对Rapamycin的反应也存在明显的差异。
结论静脉注射Rapamycin可以对MPTP诱导的小鼠PD模型产生明显的治疗作用; Rapamycin不但可以减少DA能神经元死亡,还能够恢复DA能神经元的功能,从而增加了DOPAC的含量;Rapamycin的治疗作用可能与促进异常积聚的蛋白α-synuclein的降解有关。
Part I Autophagic pathway and probable mechanism in the degradation of mutantα-synuclein in PC12 cells
OBJECTIVE: The accumulation of mutantα-synuclein plays a major role and morphologic evidence of autophagy has been reported in Parkinson disease. We aim to observe the effect of mutantα-synuclein (A30P) in autophagic programmed cell death by transfected PC12 cells and explored its probable role and pathway in PD.
METHODS: We constructed definite PC12 cells which were transfected mutantα-synuclein (A30P) at first and administrate MPP+, Rapamycin and Wortmanin to transfected PC12 cells with mutantα-synuclein. We not only detected proliferative activity of cells with MTT method but also observed the ultrastructure changes of cells and expression ofα-synuclein in different circumstance by Transmission electron microscopy (TEM), Western Blotting and and the level of SOD.
RESULTS: Mutantα-synuclein (A30P) leading to PC12 cells death involvesα-synuclein accumulation, membrane lipid oxidation, and loss of plasma membrane integrity. Mutantα-synuclein (A30P) mediates the toxicity of MPP+. Rapamycin, an inducer of autophagy, reduces the aggregation ofα-synuclein in transfected cells. Meanwhile, Wortmanin, an inhibitor of autophagy, promotes the aggregation ofα-synuclein in transfected cells and induces cells to die.
CONCLUSION: The abnormal aggregation ofα-synuclein induces autophagic programmed cell death in PC12 cells and mutantα-synuclein (A30P) mediates the toxicity of MPP~+. Meanwhile, Rapamycin may reduce the aggregation ofα-synuclein in transfected cells by activation of autophagic pathway.
Part II Mutant -synuclein (A30P)are degraded by autophagic pathway and mechanism under oxidative stress
Objective The accumulation of mutantα-synuclein plays a major role and morphologic evidence of autophagy has been reported in Parkinson disease. We aim to observe the effect of MPP~+ to mutantα-synuclein (A30P) in autophagic programmed cell death by transfected PC12 cells and explored its probable role and degradative pathway in PD. Method We constructed definite PC12 cells which were transfected mutantα-synuclein (A30P) at first and administrate MPP~+ to establish the the model of PD with cells under oxidative stress. Rapamycin and Wortmanin were administered to transfected PC12 cells with mutantα-synuclein respectively . We not only detected proliferative activity of cells with MTT method but also observed the ultrastructure changes of cells by Transmission electron microscopy (TEM). Meanwhile expression ofα-synuclein and LC3 in different circumstance was examined by Western Blotting. Moreover, the levels of CAT and SOD in cell cultures were also compared in order to discuss the relation between oxidative stress and autophagy. Results MPP~+ to mutantα-synuclein (A30P) leads to PC12 cells death by means of autophagy involvesα-synuclein accumulation, membrane lipid oxidation, and loss of plasma membrane integrity. Mutantα-synuclein (A30P) mediates the toxicity and enhances the sensitivity of MPP~+ . Rapamycin, an inducer of autophagy, reduces the aggregation ofα-synuclein in transfected cells. Meanwhile, Wortmanin, an inhibitor of autophagy, promotes the aggregation ofα-synuclein in transfected cells and induces cells to die. Conclusion Mutantα-synuclein (A30P) mediates the toxicity of MPP~+. Meanwhile, inducer of autophagy-Rapamycin may reduce the aggregation ofα-synuclein in transfected cells by activation of autophagic pathway.
Part III Therapeutic effect and probable mechanisim of Rapamycin on MPTP-induced parkinsonism in mice
OBJECTIVE: To investigate the effects of inducer of autophagy-Rapamycin on the functional and morphological outcome in a mice model of Parkinson s disease (PD) rendered by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).
BACKGROUND: In neurodegenerative disorders such as PD, autophagy participates in the cell death process of dopaminergic neuron.α-Synuclein is one of the major components of Lewy bodies and Lewy neuritis and mutation ofα-synuclein such as a-synuclein mutants (A53T and A30P) may be involved in the development of familial PD. Our previous study demonstrated that Rapamycin may induce autophagy and decrease aggregation ofα-synuclein and cell death.
METHODS: Male C57BL mice were treated with Rapamycin(3mg/kg) by i.v for 7 days after MPTP administration(30mg/kg.14d), and were compared with saline-treated PD mice and normal control group. Immunohistochemistry and Western blot were used to detect the alterations of PD biomarker including tyrosine hydroxylase (TH), and the level of autophagy was investigated by microtubule-associated protein light chain 3(LC3) andα-synuclein cleavage. In addition, monoamine neurotransmitters in the striatum of mice were measured by the high performance liquid chromatography (HPLC).
RESULTS: TH immunohistochemistry indicated that the number of dopaminergic neurons in the substantia nigra was increased in Rapamycin-treated mice compared with saline-treated mice (p=0.003). Western blot demonstrated the similar TH protein expression in striatum as the number of dopaminergic neurons.α-Synuclein was markedly decreased in Rapamycin-treated mice compared with the NS-treated mice(p=0.004) and LC3 was markedly increased in Rapamycin-treated mice compared with the NS-treated mice(p=0.003). Meanwhile, DAT and VMAT-2 were markedly decreased in Rapamycin-treated and NS-treated mice compared with control group. Although the degree was different, DAT and VMAT-2 were markedly increased in Rapamycin-treated compared with NS-treated mice. The concentrations of striatal dopamine and its metabolite DOPAC compared to the normal mice were decreased significantly in other groups. Rapamycin-treated mice minimized the reduction of DOPAC compared with the NS-treated mice (p=0.001).
CONCLUSIONS: These results showed that Rapamycin is able to rescue the dopaminergic neurons in different doses and reverses the loss of DOPAC through activation of autophagy-lysosome pathway, and it may be a promising therapeutic agent in PD.
引文
1. Zhang ZX, Roman G.C, Hong Z, et al. Parkinson's disease in China: prevalence in Beijing,Xian,and Shanghai. Lancet. 2005; 365(9459):595-597.
2. de Lau L.M. and Breteler M.M. Epidemiology of Parkinson's disease. Lancet Neurol. 2006; 5(6):525-535.
3. Langston JW, Ballard P, Tetrud JW, et al. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219(4587):979-980.
4. Heikkila RE, Hess A, and Duvoisin RC. Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice. Science.1984; 224 (4656): 1451-1453.
5. Przedborski S, Tieu K, Perier C, et al. MPTP as a mitochondrial neurotoxic model of Parkinson's disease. J Bioenerg Biomembr. 2004; 36(4):375-379.
6. Greenamyre JT, Betarbet R, and Sherer TB. The rotenone model of Parkinson's disease: genes, environment and mitochondria. Parkinsonism Relat Disord. 2003; 9 Suppl 2:S59-64.
7. Thiruchelvam M, McCormack A, Richfield EK, et al. Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype. Eur J Neurosci. 2003; 18(3):589-600.
8. Payami H. and Zareparsi S. Genetic epidemiology of Parkinson's disease. J Geriatr Psychiatry Neurol. 1998; 11(2):98-106.
9. Cuervo A.M., Stefanis L., Fredenburg R., et al. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004; 305 (5688):1292-1295.
10. Foroud T. LRRK2: both a cause and a risk factor for Parkinson disease? Neurology. 2005; 65(5):664-665.
11. Chung KK, Dawson VL, Dawson TM. The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders. Trends Neurosci. 2001; 24(11 Suppl): S7-14.
12. Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 2001; 292(5521): 1552-5.
13. Shastry BS. Neurodegenerative disorders of protein aggregation. Neurochem Int. 2003; 43(1): 1-7.
14.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志. 2008; 41(1): 51-56.
15. Yang YP, Liu KY, Qian JJ, et al. The abnormal aggregation of alpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007; 14 (Suppl. 1):197.
16. Rott R, Szargel R, Haskin J,Shani V, Shainskaya A, Manov I, Liani E, Avraham E, Engelender S. Monoubiquitination ofα-synuclein by SIAH promotes its aggregation in dopaminergic cells. J Biol Chem 2007.
17. Simone Engelender. Ubiquitination ofα-synuclein and autophagy in Parkinson’s disease. Autophagy 4:3, 1-3,2008.
18. Nonaka T, Iwatsubo T, Hasegawa M. Ubiquitination ofα-synuclein. Biochemistry 2005; 44:36 -8.
19. Lee JT, Wheeler TC, Li L, Chin LS. Ubiquitination of {alpha}-synuclein by Siah promotesα-synuclein aggregation and apoptotic cell death. Hum Mol Genet 2007.
20. B Ravikumar, C Vacher and Z Berger et al., Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36 (2004); 585–595.
21. Z Berger, B Ravikumar and FM Menzies et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 15 (2006); 433–442.
22. Carmichael J, KL Sugars, YP Bao, and DC Rubinsztein. Glycogen synthase kinase-3 inhibitors prevent cellular polyglutamine toxicity caused by the Huntington’s disease mutation. J. Biol. Chem. 2002; 277:33791–33798.
23. Berger Z, Ttofi EK, Michel CH, et al. Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway. Hum Mol Genet 2005; 14:3003-11.
24. S Sarkar, RA Floto and Z Berger, et al. Lithium induces autophagy by inhibiting inositol monophosphatase, J Cell Biol . 2005; 170:1101–1111.
25. Sovan SD, Rubinsztein C. Inositol and IP3 Levels Regulate Autophagy. Autophagy2006; 2:2, 132-134.
26. Sarkar S, Perlstein EO, Imarisio S, et al. Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat. Chem. Biol. 2007; 3:331–338.
27.Mizushima N, Levine B, Cuervo AM, et al. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069-75.
28. Fimia GM, Stoykova A, Romagnoli A, et al. Ambra1 regulates autophagy and development of the nervous system. Nature. 2007;447:1121-5.
29. Pandey UB, Nie Z, Batlevi Y, et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 2007;447:859-63.
30. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441:880-4.
31. Hara T, Nakamura K, Matsui M, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441:885-9.
32. Levine B, Kroemer G.. Autophagy in the pathogenesis of disease. Cell. 2008;132:27-42.
33. Komatsu M, Waguri S, Koike M, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131:1149-63.
34. Rubinsztein DC, Gestwicki JE, Murphy LO, et al. Potential therapeutic applications of autophagy. Nat Rev Drug Discov. 2007;6:304-12.
1. Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation period. Nature 2004; 432:1032–1036
2. Anglade P, Vyas S, Javoy-Agid F, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol. Histopathol.1997; 12(1):25–31
3. Stefanis L, Larsen KE, Rideout HJ, et al. Expression of A53T mutant but not wild-type a-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation, loss of dopamine release, and autophagic cell death. Neurosci. 2001; 21: 9549–9560
4. Spillantini M, Schmidt M, Trojanowski J, et al. a-synuclein in Lewy bodies. Nature1999; 388:839-840
5. Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusionbody formation in a-synuclein mice: Implications for neurodenerative disorders. Science; 2000; 287(5456):1265-1269
6. Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000; 290(5493): 985-989
7.钱进军,程言博,刘春风,杨亚萍,刘康永.人SNCA基因真核表达载体的构建及其在PC12细胞中的表达.细胞与分子免疫学杂志. 2008; 24(1): 23-26.
8. Kruger R, Kuhn W, Muller T, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet. 1998; 18:106-108
9.Charleen TC. Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 2006; 65:423-432.
10.Tanida I, Minematsu-Ikeguchi N, Ueno T, Kominami E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy. 2005;1:84-91
11.Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013
12.Shao Y, Gao Z, Marks PA ,et al. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A. 2004; 101(52): 18030-5.
13.Furuya N, Liang XH, and LevineB. 2004. Autophagy and cancer. In autophagy.D.J. Klionsky,editor. Landes Bioscience.Georgetown,Texas,USA.244-253
14. Fujiwara H, Hasegawa M, Dohmae N, et al. ?a-synuclein is phosphorylated in synucleinopathies. Nat cell Biol, 2002; 4: 160-164
15. Hsu LJ, Sagara Y, Arroyo A, et al. alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 2000; 157: 404-410
16. Lotharis J, Barg S, Wiekop P, et al. Effect of a-synuclein on dopamine homeostasis in a new human mesencephalic line. Biol Chem. 2002; 277:38884-38894
17. Dalfo’E, Gomez-Isla T, Rosa JL, et al. Abnormal a-synuclein interactions with Rat proteins in a-synuclein A30P transgenic mice. Neuropathol Exp Neurol, 2004; 63: 302-313
18. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress inneurodegenerative diseases. Nature. 2006; 443(7113): 787-795
19. Rojo AI, Montero C, Salazar M, et al. Persistent penetration of MPTP through the nasal route induces Parkinson's disease in mice. Euro Neurosci 2006; 24:1874-1884
20.Michel PP, Alvarez-Fischer D, Guerreiro S, et al. Role of activity-dependent mechanisms in the control of dopaminergic neuron survival. Neurochem 2007; 101: 289-297
21. Turnbull S, Tabner BJ, El-Agbaf OM, et al. alpha-Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med.2001; 30(10):1163-1170
22. Lovell MA, Xiong S, Xie C, et al. Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. Alzheimers Dis.2004; 6: 659-671.
23. Petrucelli L, Dawson TM. Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system. Ann Med 2004;36:315–320.
24. Song DD, Shults CW, Sisk A, et al. Enhanced substantia nigra mitochondrial pathology in human [alpha]-synuclein transgenic mice after treatment with MPTP. Exp. Neurol. 2004; 186: 158-172
25. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290:1717–1721.
26. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
27. Shimizu S, Kanaseki T, Mizushima N. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004; 6(12): 1221-8.
28. Mizushima N, Sugita H, Yoshimori T, et al. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem. 1998; 273(51): 33889-92.
29. Kanzama T, Zhang L, Xiao L, et al. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3 Oncogene. 2005; 24: 980-991
30. Li Yu, Fengyi Wan,Sudeshna,Dutta, et al. Autophagic programmed cell death by selective catalase degradation. PNAS 2006; 103: 4952-4957
31. Abeliovich H, Dunn WJ, Kim J, et al. Dissection of autophagosome biogenesis into distinct nucleation and expansion steps. Cell Biol. 2000; 151: 1025–1034.
32. Sovan S, Janet E D, Zebo H, et al. Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin andα-Synuclein. Biol. Chem., 2007; 282; 5641-5652.
33. Stefanis L, Larsen KE, Rideout HJ, et al. Expression of A53 T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 2001; 21:9549–9560
34. Chan L, Gaston R, Hariharan S. Evolution of immunosuppression and continued importance of acute rejection in renal transplantation. Am. J. Kidney Dis., 2001;38: 2–9.
35. Wellington CL, Singaraja R, Ellerby L, et al. Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. Biol. Chem., 2000; 275: 19831–9838
36. Beth L, Junying Y. Autophagy in cell death: an innocent convict? Clin Invest 2005; 115:2679-2688
37. Snyder H, Mensah K, Theisler H, et al. Aggregated monomeric alpha-synuclein bind to the 6S’proteasomal protein and inhibit proteasomal function. Biol Chem. 2003; 278(14): 11753-759
38. Tanaka Y, Engelender S, Igarashi et al. Inducible expression of mutant-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependant apoptosis. Hum Mol Genet. 2001; 10(9): 919-926
39.Thorburn Andrew. Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis.2008; 13(1):1-9
40. Iwamaru A, Kondo Y, Iwado E, et al. Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells. Oncogene.2007; 26(13):1840-1851
41.van der Vaart Aniek , Mari Muriel, Reggiori Fulvio. A Picky Eater: Exploring the Mechanisms of Selective Autophagy in Human Pathologies.Traffic 2008; 9(3):281-289
42. Ravikumar Brinda, Stewart Abigail, Kita Hiroko, et al. Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy.Human Molecular Genetics.2003;12(9):985-994
1. Spillantini M, Schmidt M, Trojanowski J, et al.α-synuclein in Lewy bodies.Nature1999; 388:839-840
2. Anglade P, Vyas S, Javoy-Agid F,et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol. Histopathol.1997; 12(1):25–31
3. Stefanis L, Larsen KE, Rideout HJ, et al. Expression of A53T mutant but not wild-typeα-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation, loss of dopamine release, and autophagic cell death. Neurosci. 2001; 21: 9549–9560
4.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志. 2008; 41(1): 51-56
5.Yang YP, Liu KY, Qian JJ, et al. The abnormal aggregation of alpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007 ; 14 (Suppl. 1):197
6. Charleen TC. Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 2006; 65:423-432.
7.Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013
8.Shao Y, Gao Z, Marks PA, et al. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A. 2004; 101(52): 18030-5.
9.Furuya N, Liang XH, and Levine B. 2004. Autophagy and cancer. In autophagy.D.J. Klionsky,editor. Landes Bioscience.Georgetown,Texas,USA.244-253
10.Beyer K. a-Synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol 2006; 112: 237–251.
11. Marta Martinez-Vicente, Ana Maria Cuervo. Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 2007; 6: 352–61.
12. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006; 441(7095): 880-884.
13. Noboru Mizushima1. Autophagy: process and function. Genes & Dev. 2007; 21: 2861-2873
14.Beth Levine and Guido Kroemer. Autophagy in the Pathogenesis of Disease. Cell.2008;132:28-42.
15. Lotharis J, Barg S, Wiekop P, et al. Effect ofα-synuclein on dopamine homeostasis in a new human mesencephalic line. Biol Chem, 2002; 277:38884-38894
16. Dalfo’E, Gomez-Isla T, Rosa JL, et al. Abnormalα-synuclein interactions with Rat proteins inα-synuclein A30P transgenic mice. Neuropathol Exp Neurol, 2004; 63: 302-313
17. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443(7113): 787-795
18.Turnbull S, Tabner BJ, El-Agbaf OM, et al. alpha-Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med.2001; 30(10):1163-1170
19. Rojo AI, Montero C, Salazar M, et al. Persistent penetration of MPTP through the nasal route induces Parkinson's disease in mice. Euro Neurosci 2006; 24:1874-1884
20.Michel PP, Alvarez-Fischer D, Guerreiro S, et al. Role of activity-dependent mechanisms in the control of dopaminergic neuron survival. Neurochem 2007; 101: 289-297
21. Lehmensiek V, Tan EM, Schwarz J, et al. Expression of mutant alpha-synucleins enhances dopamine transporter-mediated MPP+ toxicity in vitro. Neuroreport.2002; 13:1279–1283.
22. . Rojo AI, Montero C, Salazar M, et al. Persistent penetration of MPTP through the nasal route induces Parkinson's disease in mice. Euro Neurosci 2006; 24:1874-1884
23. Petrucelli L, Dawson TM. Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system. Ann Med 2004;36:315–320.
24.Qian JJ, Cheng YB,Yang YP, Mao CJ, Qin ZH, Li K, Liu CF. Differential effects of overexpression of wild-type and mutant humanα-synuclein on MPP+-induced neurotoxicity in PC12 cells. Neurosci Lett. (Acceptted , DOI information: 10.1016/j.neulet.2008.02.021).
25. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
26. Shimizu S, Kanaseki T, Mizushima N. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004; 6(12): 1221-8.
27. Kanzama T, Zhang L,Xiao L, et al. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3 Oncogene. 2005; 24: 980-991
28. Li Yu, Fengyi Wan, SudeshnaDutta, et al. Autophagic programmed cell death by selective catalase degradation. PNAS 2006; 103: 4952-4957
29. ?sa B. Gustafsson, Roberta A. Gottlieb.The role of autophagy in cardioprotection. YJMCC-06240; No. of pages: 8; 4C: 2 .2008.
30. Lovell MA, Xiong S, Xie C, et al. Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. Alzheimers Dis.2004; 6: 659-671.
31. Song DD, Shults CW, Sisk A, et al. Enhanced substantia nigra mitochondrial pathology in human [alpha]-synuclein transgenic mice after treatment with MPTP. Exp. Neurol. 2004; 186: 158-172
32.Beyer K. a-Synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol 2006; 112: 237–251.
33. Koichi Wakabayashi, Kunikazu Tanji, Fumiaki Mori1 and Hitoshi Takahashi.The Lewy body in Parkinson’s disease: Molecules implicated in the formation and degradation of a-synuclein aggregates. Neuropathology 2007; 27, 494–506.
34. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 1997;22:267-72
35.Tassa A, Roux MP, Attaix D, Bechet DM. Class III phosphoinositide 3-kinase-Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem J 2003;376:577-86
36. Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P. Distinct classes of phosphatidylinositol 3-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 2000;275:992-98
37 Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005, 120(2): 237-248.
38.Sophie Pattingre, Lucile Espert, Martine Biard-Piechaczyk, et al. Regulation ofmacroautophagy by mTOR and Beclin 1 complexes. Biochimie 90 (2008) 313-323.
39.Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell, 2004; 6(4): 463-477.
40. Uttenweiler A, Schwarz H, Neumann H, et al. The vacuolar transporter chaperone (VTC) complex is required for microautophagy. Mol. Biol. Cell, 2007; 18(1): 166 - 175.
41.Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol, 2005; 169(3): 425-434.
42. Rubinsztein DC, Gestwicki JE; Murphy LO, and Klionsky DJ. Potential therapeutic applications of autophagy. Nat. Rev. Drug Discov. 2007;6:304–312.
43.Sovan S, Janet ED, Zebo H,et al. Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin andα-Synuclein. Biol. Chem., 2007; 282; 5641-5652.
44. Zhu J-H, Kulich SM, Oury TD, Chu CT. Cytoplasmic aggregates of phosphorylated extracellular signal-regulated kinase in Lewy body diseases. Am J Pathol 2002;161:2087-98
45. Chu CT, Levinthal DJ, Kulich SM, Chalovich EM, DeFranco DB. Oxidative neuronal injury. The dark side of ERK1/2. Eur J Bichem 2004;271:2060-66
46. Rodriguez-Enriquez S, Kim I, Currin RT, Lemasters JJ. Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy 2006;2:39-46
47. Zahniser N.R. and Doolen S. Chronic and acute regulation of Na+/Cl- -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther, 2001; 92(1):21-55.
48.Wersinger C. and Sidhu A. Attenuation of dopamine transporter activity by alpha-synuclein. Neurosci Lett, 2003; 340(3):189-192.
49.Wersinger C; Prou D; Vernier P; et al. Modulation of dopamine transporter function by alpha-synuclein is altered by impairment of cell adhesion and by induction of oxidative stress. Faseb J, 2003; 17(14):2151-2153.
1.Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000; 290(5493): 985-989
2. Polymeropoulos MH. Autosomal dominant Parkinson's disease and alpha-synuclein. Ann Neurol 1998; 44:S63–S64.
3.Stefanis L, Larsen KE, Rideout HJ, et al. Expression of A53 T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 2001; 21:9549–9560.
4.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志. 2008; 41(1): 51-56
5.Yang YP, Liu KY, Qian JJ, et al. The abnormal aggregation of alpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007; 14 (Suppl. 1):197
6. Anglade P, Vyas S, Javoy-Agid F,et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol. Histopathol.1997; 12(1):25–31
7. Hoffman BJ, Hansson SR, Mezey E, et al. Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Front Neuroendocrinol,1998;19(3):187-231
8. Liu YJ, Robert HE. The role of vesicular transport proteins in synaptic transmission and neural degeneration. Anns Neurosci. 1997; 20:125-156
9.Uhl GR. Hypothesis: The role of dopaminergic transporters in selectivevulnerability of cell in Parkinson’s disease. Ann Neurology.1998; 43(5):555-560
10.Kitayama S, Wang JB, Uhl GR. Dopamine transporter mutants selectively enhance MPP+ transport. Synapse.1993; 15(1):58-62
11.Liu Y, Peter D, Roghani A, et al. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell. 1992;70(4):539-551
12.Trimbele WS, Linial M, Scheller RH. Cellular and molecular biology of the presynaptic nerve terminal. Annu Rev Neurosci.1991; 14:93-122
13.Brooks DJ, Frey KA, Marek KL, et al. Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease. Exp Neurol, 2003, 184 Suppl 1:S68-79.
14.Choi HJ, Lee SY, Cho Y, et al. Inhibition of vesicular monoamine transporter enhances vulnerability of dopaminergic cells: relevance to Parkinson's disease. Neurochem Int, 2005; 46(4):329-335.
15. German DC, Liang CL, Manaye KF, et al. Pharmacological inactivation of the vesicular monoamine transporter can enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of midbrain dopaminergic neurons, but not locus coeruleus noradrenergic neurons. Neuroscience, 2000; 101(4):1063-1069.
16. Liu Y. and Edwards RH. The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annu Rev Neurosci, 1997; 20:125-156.
17.Liang CL, Nelson O, Yazdani U, et al. Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: human midbrain dopamine neurons. J Comp Neurol, 2004, 473(1):97-106.
18.Sanghera MK, Manaye K, McMahon A, et al. Dopamine transporter mRNA levels are high in midbrain neurons vulnerable to MPTP. Neuroreport. 1997; 8(15):3327-3331.
19.Storch1 A, Ludolph1 AC, and Schwarz J. Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration .J Neural Transm 2004;111: 1267–1286
20.Won Yong Lee, Eun Ah Lee, Mi Young Jeon, et al. Vesicular monoaminetransporter-2 and aromatic L-amino acid decarboxylase gene therapy prevents development of motor complications in parkinsonian rats after chronic intermittent L-3,4-dihydroxyphenylalanine administration Experimental Neurology 2006; 197:215-224
21.Won Yong Lee, Jin Woo Chang, Nicole L, et al. Vesicular Monoamine Transporter-2 and Aromatic L-Amino Acid Decarboxylase Enhance Dopamine Delivery after L-3 , 4-Dihydroxyphenylalanine Administration in Parkinsonian Rats. Neuroscience. 1999; 19(8):3266-3274
22.Jannine G. Truong, Kristi S Rau, Glen R Hanson, et al. Pramipexole increases vesicular dopamine uptake: implications for treatment of Parkinson's neurodegeneration. European Journal of Pharmacology 2003; 474: 223-226
23.Sun M, Kong L, Wang X, et al. Coexpression of tyrosine hydroxylase, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter 2 from a helper virus-free herpes simplex virus type 1 vector supports high-level, long-term biochemical and behavioral correction of a rat model of Parkinson's disease. Human Gene Therapy. 2004; 15(12):1177-96
24.Kumar MJ and Andersen JK. Perspectives on MAO-B in aging and neurological disease: where do we go from here? Mol Neurobiol, 2004; 30: 77-89
25.R.R. Gainetdinov, F. Fumagalli,Y.M. Wang, et al. Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice. Neurochem1998; 70: 1973–1978.
26.D.C. German; C.L. Liang; K.F. Manaye; K. Lane and P.K. Sonsalla, Pharmacological inactivation of the vesicular monoamine transporter can enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of midbrain dopaminergic neurons, but not locus coeruleus noradrenergic neurons, Neuroscience 2000; 101: 1063–1069.
27.J.G. Nutt. Long-term L-DOPA therapy: challenges to our understanding and for the care of people with Parkinson's disease, Exp. Neurol. 2003; 184:. 9–13
28.J.G. Nutt, J.H. Carter, E.S. Lea et al. Evolution of the response to levodopa during the first 4 years of therapy, Ann. Neurol. 2002; 51: 686–693.
29.R.G. Staal and P.K. Sonsalla, Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata, J. Pharmacol. Exp. Ther. 2000; 293: 336–342.
30.Carlsson C,Winkler C, Burger N, Muzyczka R.J, Mandel A. Cenci and A. Kirik, Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors, Brain 2005; 128:. 559–569.
31.Moszczynska A, Saleh J, Zhang H, et al. Parkin Disrupts theα-Synuclein/Dopamine Transporter Interaction: Consequences Toward Dopamine-induced Toxicity. Journal of Molecular Neuroscience. 32(3):217-227, July 2007.
32. Chen MK, Kuwabara H, Zhou Y, et al. VMAT2 and dopamine neuron loss in a primate model of Parkinson's disease. Journal of Neurochemistry. 105(1):78-90, April 2008.
33. Spillantini M, Schmidt M, Trojanowski J, et al.α-synuclein in Lewy bodies. Nature1999; 388:839-840
34. Fujiwara H, Hasegawa M, Dohmae N, et al. ?α-synuclein is phosphorylated in synucleinopathies. Nat cell Biol, 2002; 4: 160-164
35. Hsu LJ, Sagara Y, Arroyo A, et al. alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol, 2000; 157: 404-410
36. Petrucelli L, Dawson TM. Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system. Ann Med 2004; 36:315–320.
37. Song DD, Shults CW, Sisk A, et al. Enhanced substantia nigra mitochondrial pathology in human [alpha]-synuclein transgenic mice after treatment with MPTP. Exp. Neurol. 2004; 186: 158-172
38.Lee FJ, Liu F, Pristupa ZB, Niznik HB. Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. Faseb J 2001;15:916-26
39.Gomez-Santos C, Ferrer I, Santidrian AF, Barrachina M, Gil J, Ambrosio S. Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. J Neurosci Res 2003;73:341-50
40.Sulzer D, Bogulavsky J, Larsen KE, et al. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci U S A 2000;97:11869-74
41. Mizushima N, Sugita H, Yoshimori T, et al. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy.J Biol Chem. 1998; 273(51): 33889-92.
42. Abeliovich H, Dunn WJ, Kim J, et al. Dissection of autophagosome biogenesis into distinct nucleation and expansion steps. Cell Biol. 2000; 151: 1025–1034.
43. Sovan S, Janet ED, Zebo H, et al. Trehalose, a Novel mTOR-independent Autophagy Enhancer , Accelerates the Clearance of Mutant Huntingtin andα-Synuclein. Biol. Chem. 2007; 282; 5641-5652.
44. Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013
45. Huang WP and Klionsky DJ. Autophagy in yeast: a review of the molecular machinery. Cell Struct Funct 2002; 27:409–420.
46. Klionsky DJ and Ohsumi Y. Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol 1999; 15:1–32.
47. Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 2001; 152:657–668.
48. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290:1717–1721.
49. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
50. Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M and Ohzumi Y. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 2000; 150:1507–1513.
51. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
52. Ohsawa Y, Isahara K, Kanamori S, Shibata M, Kametaka S, Gotow T, et al. An ultrastructural and immunohistochemical study of PC12 cells during apoptosis induced by serum deprivation with special reference to autophagy and lysosomal cathepsins. Arch Histol Cytol 1998; 61:395–403.
53. Levine B and Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6:463–477.
54. Shimizu S, Kanaseki T, Mizushima N, et al. Role of Bcl-2 family proteins in a 2004; 6(12): 1221-8.
55. Kanzama T, Zhang L, Xiao L, et al. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3 Oncogene. 2005; 24: 980-991
56.Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013.
57. Chan L, Gaston R, Hariharan S. Evolution of immunosuppression and continued importance of acute rejection in renal transplantation. Am. J. Kidney Dis., 2001;38: 2–9.
58. Wellington CL, Singaraja R, Ellerby L, et al. Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. Biol. Chem., 2000; 275: 19831–9838
1. Moore DJ, West AB,st, Dawson VL: Molecular pathophysiology of Parkinson’s disease. Annu. Rev. Neurosci. 2005, 28: 57-87
2. Cookson MR, Brug MV, Cell system and the toxic mechanism(s) ofα-synuclein. Experimental Neurology, 2008,209: 5-11
3. Liu H, Wang XZ, Alpha-synuclein and Parkinson disease. Neural Regen Res, 2007, 2: 39-43
4. Li HT., Du HN, Tang L, et al. Structural transformation and aggregation of human alpha-synuclein in trifluoroethanol: non-amyloid component sequence is essential and beta-sheet formation is prerequisite to aggregation, Biopolymers, 2002,64: 221-226
5. Zarranz JJ, Lezcano E, Alegre J, et al. The new mutation, E46K, ofα-synuclein causes Parkinson and Lewy Body Dementia. Ann Neurol 2004,55: 164-173
6. Winkler S, Hagenah J, Klein C, et al.α-Synuclein and Parkinson disease susceptibility. Neuology, 2007,69: 1345-50
7. Parsian AJ, Patra B, Parsian A, et al. Association ofα-synuclein gene haplotypes with Parkinson’s disease. Parkinsonism and Related Disorders,2007,13:343-47
8. Maraganore DM, Andrade MD, Farrer MJ, et al. Collaorative analysis ofα-synuclein gene promoter variability and Parkinson disease. JAMA 2006;96: 661-670
9.何延波,陈彪.α-synuclein基因多态性与帕金森病.中华神经科杂志.2007;2:133-135
10. Crowther RA, Daniel SE, Goedert M, Characteristerisation of isolated alpha-synuclein filaments from substantia nigra of Parkinson’s disease brain, Neurosci. Lett., 2000;92: 128-130
11. Miake H, Mizusawa H, Iwatsubo T, et al. Biochemical characterization of the core structure of alpha-synuclein filaments. Biol. Chem. 2002;277: 19213-19219
12. Zhang F, Lin XJ, Hu HY, et al. Assembly ofα-synuclein fibrils in nanoscale studied by peptide truncation and AFM. Biochemical and Biophysical Research Communications. 2008;368: 388-394
13. Hoyer W, Cherny D, Subramaniam V, et al. Rapid self-assembly of alpha-synuclein observed by in situ atomic force microscopy, J. Mol. Biol., 2004,340: 127-139
14. Kim M, Jung W, Hahn JS, et al. Impairment of microtubule system increasesα-synuclein aggregation and toxicity. Biochemical and Biophysical Research Communications. 2008;365: 628-635
15. Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003;300: 636-640
16. Lindersson E, Lundvig D, Petersen C, et al. p25alpha stimulates alpha-synuclein aggregation and is colocalized with aggregated alpha-synuclein in alpha-synucleinopathies, J. Biol. Chem. 2005,280: 5703-5715
17. Chen MK, Kuwabara H, Zhou,Y, et al. VMT2 and dopamine neuron loss in a primate model of Parkinson’s disease. Journal of Neurochemistry. 2008; 105(1): 78-90
18. Liu CW, Giasson BI, Thomas PJ, et al. A precipitating role for Truncatedα-synuclein and Proteasome inα-synuclein Aggregation.Biol.Chem.2005;280: 22670-22678
19. Kasai T, Tokuda T, Mizuno T, et al. Cleavage of nomal and pathological forms ofα-synuclein by neurosin in vitro, Neurosci. Lett. (2008), doi: 10.10.16/j. neulet 2008 02. 057
20. Dufty BM, Wamer LR, Rohn TT, et al. Calpain-cleavage ofα-synuclein. The American Journal of Pathology. 2007;170: 1725-1738
21. Iwatsubo T , Pathological biochemistry ofα-syncleinopathy , Neuropathology 2007,27: 474-478
22. Kim HY, Heise H, Fernandez CO, et al. correlation of amyloid fibril beta-structure with the unfolded state of alpha-synuclein, Chembiochem, 2007, 8: 1671-1674
23. Bharathi, Indi SS, Rao KSJ: Copper- and iron-induced differential fibril formation inα-synclein: TEM study. Neuroscience Letters. 2007: 424: 78-82
24. Bharathi and Rao KSJ: Thermodynamics imprinting reveals differential binding of metals toα-synuclein: Relevance to Parkinson’s disease. Biochemical and biophysical research communications. 2007;359: 115-120.
25. Giannakis E, Pacifico J, Smith DP, et al. Dimeric structures ofα-synuclein bind preferentially to lipid membranes. Biochim. Biophys. Acta. 2008;1778: 1112-1119
26. Danzer KM, Haasen D, Anne R, et al. Different species ofα-synuclein oligomers induce calcium influx and seeding. The Journal of Neuroscience. 2007;27: 9220-9232
27. Demuro A, Parker I, Glabe CG, et al. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. Biol. Chem. 2005; 280: 17294-17300
28. Lashuel HA, Lansbury PT Jr. Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins? Q. Rev. Biophys 2006; 39: 167-201
29. Green JD, Kreplak L, Goldsbury C, et al. Atomic force reveals defects within mica supported lipid bilayers induced by the amyloidogenic human amylin peptide. Biol Chem 2004; 342: 877-887
30. Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked toneurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000; 290(5493): 985-989
31. Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation inα-synuclein mice: Implications for neurodenerative disorders. Science; 2000; 287(5456):1265-1269
32. Tanaka Y , Engelender S , Igarashi et al. Inducible expression of mutant-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependant apoptosis. Hum Mol Genet. 2001; 10(9): 919-926
33. Tashiro M, Kojima M, Kihara H, et al., Characterization of fibrillation process ofα-synuclein at the initial stage. Biochem. Biophys. Res. Commun., 2008,369: 910-914
34. Kamiyoshihara T, Kojima M, Uéda K, et al. Observation of multiple intermediates inα-synuclein fibril formation by singular value decomposition analysis, Biochem. Biophys. Res. Commun. 2007,355: 398-403
35. Senior SL, Ninkina N, Deacon R, et al. Increased striatal dopamine release and hyperdopaminergic-like bahaviour in mice lacking both alpha-synuclein and gamma-synuclein. European Journal of Neuroscience. 2008; 27(4): 947-957
36. Moszczynska A, Saleh J, Zhang HY, et al. Parkin disrupts the alpha synuclein/Dopamine Transporter Interaction: Consequences Toward Dopamine-induced Toxicity. Journal of Molecular Neuroscience. 2007; 32(3):217-227
37. Li W, Lesuissem C, Xu Y, et al. Stabilization of alpha-synuclein protein with aging and familial Parkkinson’s disease-linked A53T mutation. Neurosci. 2004;24:7400-7409.
38. Clough RL, Stefanis L, A novel pathway for transcripitional regulation ofα-synuclein. The FASEB Journal, 2007,21: 596-607
39. Gomez-Santos C., Barrachina M., Gimenez-Xavier P., et al., Induction of C/EBP beta and GADD153 expression by dopamine in human neuroblastoma cells. Relationship with alpha-synuclein increases and cell damage. Brain Res. Bull., 2005; 65: 87-95
40.Chiba-Falek O, Kowalak JA, Smulson ME, et al. Regulation ofα-synucleinexpression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of SNCA gene. American Journal of Human Genetics, 2005; 76: 478-492
41. Spillantini M, Schmidt M, Trojanowski J, et al.α-synuclein in Lewy bodies. Nature1999; 388:839-840
42. Fuchs J, Nilsson C, Kachergus J, et al. Phenotypic variation in a large Swedish pedigree due to SNCA dupilication and triplication. Neurology. 2007;68: 916-922
43. Rubinsztein DC, The roles of intracellular protein-degradation pathways in neurodegeneration. Nature. 2006;443: 780-786
44. Berger Z, Ravikumar B, Rubinsztein DC, et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Human Molecular Genetics. 2006;15: 433-442
45. Sarkar S, Davies J, Rubinsztein DC, et al. Trehalose, a noval mTOR-independent autophagy enhancer , accelerates the clearance of mutant huntingtin andα-synuclein. Biol.Chem. 2007;282: 5641-5652
46. Sarkar S, loto A, Rubinsztein DC, et al. Lithium induces autophagy by inhibiting inositol monophosphatase. The journal of cell biology. 2005;170: 1101-1111
47. Banhyopadhyay U, Cuervo AM, Chaperone-mediated autophagy in aging and neurodegeneration: Lessons fromα-synuclein. Experimental Gerontology. 2007;42: 120-128.
48. Shacka JJ, Roth KA, Zhang JH, The autophagy-lysosomal degradation pathway: role in neurodegenerative disease and therapy. Frontiers in Bioscience. 2008;13: 718-736
49. Pan TH, Kondo S, Le WD, et al. The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain. 2008; 1: 1-10
50. Yasuda T, Miyachi S, Y.Mizuno, Mochizuki H, et al. Neuronal specificity ofα-synclein toxicity and effect of Parkin co-expression in primates. Neuroscience. 2007;144: 743-53.
51. Martinez-Viceente M, Kaushik S, Massey AC, et al. Dopamine-modifiedα-synuclein blocks chaperone-mediated autophagy. Clin.Inves. doi:10.1172/JCI32806
52.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志.2008; 41(1): 51-56
53. Yang, YP, Liu KY, Qian JJ, et al. The abnormal aggregation of alpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007, 14 (Suppl. 1):197
54. Recchia A, Rota D, Debetto P, et al. Generation of aα-synclein-based rat model of Parkinson’s disease. Neurobiology of Disease.2008;30: 8-18.
55. Wakamatsu M, Ishii A, Iwata S, et al. Selective loss of nigral dopamine neurons induced by overexpression of truncated humanα-synclein in mice. Neurobiology of Aging. 2008; 29: 574-85.
56. Eslamboli A, Baker H, Ridley RM, et al. Long-term conseauences of human alpha-synuclein overexpression in the primate ventral midbrain. Brain.2007;130: 799-815
1. Shintani T, Klionky DJ. Autophagy in health and disease: a double-edged sword. Science, 2004, 306: 990-995.
2. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell, 2004, 6(4): 463-477.
3. Rubinsztein DC, DiFiglia M, Heintz N, et al. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy. 2005, 1(1): 11-22.
4. Noboru Mizushima1. Autophagy: process and function. Genes & Dev. 2007. 21: 2861-2873.
5. Noda T, Suzuki K, Ohsumi Y. Yeast autophagosomes: de novo formation of a membrane structure. Trends Cell Biol, 2002, 12(5): 231-235.
6. Dunn WA Jr. Studies on the mechanisms of autophagy: formation of the autophagic vacuole. J Cell Biol, 1990, 110(6): 1923-1933.
7. Yamamoto A, Masaki R, Tashiro Y, et al. Characterization of the isolation membranes and the limiting membranes of autophagosomes in rat hepatocytes by lectin cytochemistry. J Histochem Cytochem, 1990, 38(4): 573-580.
8. Mizushima N, Noda T, Yoshimori T, et al. A protein conjugation system essential for autophagy. Nature, 1998, 395(6700): 395-398.
9. Mizushima, N., and Klionsky, D. (2007). Protein turnover via autophagy: implications for metabolism. Annu. Rev. Nutr. 27, 19–40.
10. Kirisako T, Baba M, Ishihara N, et al. Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol, 1999, 147(2): 435-446.
11. Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005, 120(2): 237-248.
12. Cardenas ME, Cutler NS, Lorenz MC, et al. The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev, 1999, 13(24): 3271-3279.
13. Sophie Pattingre, Lucile Espert, Martine Biard-Piechaczyk , et al. Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie 90 (2008) 313-323.
14. Uttenweiler A, Schwarz H, Neumann H, et al. The vacuolar transporter chaperone (VTC) complex is required for microautophagy. Mol. Biol. Cell, 2007; 18(1): 166 - 175.
15. Beth Levine and Guido Kroemer. Autophagy in the pathogenesis of disease. Cell.132:28-42. 2008.
16. Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol, 2005, 169(3): 425-434.
17. Rubinsztein, D.C., Gestwicki, J.E., Murphy, et al. (2007). Potential therapeutic applications of autophagy. Nat. Rev. Drug Discov. 6, 304–312.
18. R Kiffin, C Christian, E Knecht, et al. Activation of chaperone-mediated autophagy during oxidative stress, Mol Biol Cell 15 (2004), 4829–4840.
19. Kaushik S, Massey AC, Mizushima N, et al. Constitutive Activation of Chaperone-mediated Autophagy in Cells with Impaired Macroautophagy. Mol Biol Cell. 2008 Mar 12 [Epub ahead of print].
20. Charleen T. Chu, MD, PhD. Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 2006; 65:423-432.
21. Gustafsson ?B, Gottlieb RA. Recycle or die: The role of autophagy in cardioprotection, J Mol Cell Cardiol (2008).1-8.
22. Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl), 1990, 181(3): 195-213.
23. AM Cuervo, E Bergamini, UT Brunk, et al. Autophagy and aging: the importance of maintaining“clean”cells, Autophagy 1 (2005), 131–140.
24. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 2006, 441(7095): 880-884.
25. Stefanis L. Caspase-dependent and -independent neuronal death: two distinct pathways to neuronal injury. Neuroscientist, 2005, 11(1): 50-62.
26. Lockshin RA, Zakeri Z. Apoptosis, autophagy, and more. Int J Biochem Cell Biol, 2004, 36(12): 2405-2419.
27. Pyo JO, Jang MH, Kwon YK, et al. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem, 2005, 280(21): 20722-20729.
28. Maiuri, M.C., Zalckvar, E., Kimchi, A., et al. (2007). Self-eating andself-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 8, 741–752.
29. Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest, 2005, 115(10): 2679-2688.
30. Hara T, Nakamura K, Matsui M. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice, 2006, 441(7095): 885-889.
31. Beyer K. a-Synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol 2006; 112: 237–251.
32. Marta Martinez-Vicente , Ana Maria Cuervo. Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 2007; 6: 352–61.
33. Nakai, A., Yamaguchi, O., Takeda, T., et al. 2007. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat.Med. 13: 619–624.
34. Koichi Wakabayashi, Kunikazu Tanji, Fumiaki Mori1 et al. The Lewy body in Parkinson’s disease: Molecules implicated in the formation and degradation of a-synuclein aggregates. Neuropathology 2007; 27, 494–506.
35.Yu WH, Cuervo AM, Kumar A, et al. Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol, 2005, 171(1): 87-98.
36 Nixon RA, Wegiel J, Kumar A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol, 2005, 64(2): 113-122.
37. Glabe C. Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J Mol Neurosci 2001, 17(2): 137-145.
38. Qin ZH,Wang Y,Kegel KB,et al. Autophagy regulates the processing of amino terminal huntingtin fragments. Hum Mol Genet, 2003, 12(24): 3231-3244.
39. Huang WP and Klionsky DJ. Autophagy in yeast: a review of the molecular machinery. Cell Struct Funct 2002; 27:409–420.
40. AM Cuervo, L Stefanis, R Fredenburg, et al. Impaired degradation ofmutant alpha-synuclein by chaperone-mediated autophagy, Science 305 (2004), 1292–1295.
41. Klionsky DJ and Ohsumi Y. Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol 1999; 15:1–32.
42. Mizushima N , Yamamoto A , Hatano M , et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 2001; 152:657–668.
43. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290:1717–1721.
44.AC Massey, S Kaushik, G Sovak, R Kiffin and AM Cuervo, Consequences of the selective blockage of chaperone-mediated autophagy, Proc Natl Acad Sci USA 103 (2006), 5805–5810.
45. AIwata, BE Riley, JA Johnston and RR Kopito, HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin, J Biol Chem 280 (2005), 40282–40292.
46. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
47. Kamada Y, Funakoshi T, Shintani T, et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 2000; 150:1507–1513.
48. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
49. Ohsawa Y, Isahara K, Kanamori S, et al. An ultrastructural and immunohistochemical study of PC12 cells during apoptosis induced by serum deprivation with special reference to autophagy and lysosomal cathepsins. Arch Histol Cytol 1998; 61:395–403.
50.Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013.
51.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志, 2008, 41(1): 51-56.
52.Yang, YP, Liu KY, Qian JJ, et al. The abnormal aggregation ofalpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007, 14 (Suppl. 1):197.
53. Rott R, Szargel R, Haskin J, Shani V, Shainskaya A, Manov I, Liani E, Avraham E, Engelender S. Monoubiquitination ofα-synuclein by SIAH promotes its aggregation in dopaminergic cells. J Biol Chem 2007.
54. Simone Engelender. Ubiquitination ofα-synuclein and autophagy in Parkinson’s disease. Autophagy 4:3, 1-3, 2008.
55. Nonaka T, Iwatsubo T, Hasegawa M. Ubiquitination ofα-synuclein. Biochemistry 2005; 44:36 -8.
56. Lee JT, Wheeler TC, Li L, Chin LS. Ubiquitination of {alpha}-synuclein by Siah promotesα-synuclein aggregation and apoptotic cell death. Hum Mol Genet 2007.
57. B Ravikumar, C Vacher and Z Berger et al., Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease, Nat Genet 36 (2004), 585–595.
58. Z Berger, B Ravikumar and FM Menzies et al., Rapamycin alleviates toxicity of different aggregate-prone proteins, Hum Mol Genet 15 (2006), 433–442.
59. Carmichael, J., K.L. Sugars, Y.P. Bao, and D.C. Rubinsztein. 2002. Glycogen synthase kinase-3 inhibitors prevent cellular polyglutamine toxicity caused by the Huntington’s disease mutation. J. Biol. Chem. 277:33791–33798.
60. Berger Z, Ttofi EK, Michel CH, et al. Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway. Hum Mol Genet 2005; 14:3003-11.
61. S Sarkar, RA Floto and Z Berger et al., Lithium induces autophagy by inhibiting inositol monophosphatase, J Cell Biol 170 (2005), 1101–1111.
62. Sovan Sarkar David C. Rubinsztein. Inositol and IP3 Levels Regulate Autophagy. Autophagy 2:2, 132-134, 2006.
63. Sarkar, S., Perlstein, E.O., Imarisio, S., et al. 2007. Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat. Chem. Biol. 3:331–338.
2. de Lau L.M. and Breteler M.M. Epidemiology of Parkinson's disease. Lancet Neurol. 2006; 5(6):525-535.
3. Langston JW, Ballard P, Tetrud JW, et al. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219(4587):979-980.
4. Heikkila RE, Hess A, and Duvoisin RC. Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice. Science.1984; 224 (4656): 1451-1453.
5. Przedborski S, Tieu K, Perier C, et al. MPTP as a mitochondrial neurotoxic model of Parkinson's disease. J Bioenerg Biomembr. 2004; 36(4):375-379.
6. Greenamyre JT, Betarbet R, and Sherer TB. The rotenone model of Parkinson's disease: genes, environment and mitochondria. Parkinsonism Relat Disord. 2003; 9 Suppl 2:S59-64.
7. Thiruchelvam M, McCormack A, Richfield EK, et al. Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype. Eur J Neurosci. 2003; 18(3):589-600.
8. Payami H. and Zareparsi S. Genetic epidemiology of Parkinson's disease. J Geriatr Psychiatry Neurol. 1998; 11(2):98-106.
9. Cuervo A.M., Stefanis L., Fredenburg R., et al. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004; 305 (5688):1292-1295.
10. Foroud T. LRRK2: both a cause and a risk factor for Parkinson disease? Neurology. 2005; 65(5):664-665.
11. Chung KK, Dawson VL, Dawson TM. The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders. Trends Neurosci. 2001; 24(11 Suppl): S7-14.
12. Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 2001; 292(5521): 1552-5.
13. Shastry BS. Neurodegenerative disorders of protein aggregation. Neurochem Int. 2003; 43(1): 1-7.
14.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志. 2008; 41(1): 51-56.
15. Yang YP, Liu KY, Qian JJ, et al. The abnormal aggregation of alpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007; 14 (Suppl. 1):197.
16. Rott R, Szargel R, Haskin J,Shani V, Shainskaya A, Manov I, Liani E, Avraham E, Engelender S. Monoubiquitination ofα-synuclein by SIAH promotes its aggregation in dopaminergic cells. J Biol Chem 2007.
17. Simone Engelender. Ubiquitination ofα-synuclein and autophagy in Parkinson’s disease. Autophagy 4:3, 1-3,2008.
18. Nonaka T, Iwatsubo T, Hasegawa M. Ubiquitination ofα-synuclein. Biochemistry 2005; 44:36 -8.
19. Lee JT, Wheeler TC, Li L, Chin LS. Ubiquitination of {alpha}-synuclein by Siah promotesα-synuclein aggregation and apoptotic cell death. Hum Mol Genet 2007.
20. B Ravikumar, C Vacher and Z Berger et al., Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36 (2004); 585–595.
21. Z Berger, B Ravikumar and FM Menzies et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 15 (2006); 433–442.
22. Carmichael J, KL Sugars, YP Bao, and DC Rubinsztein. Glycogen synthase kinase-3 inhibitors prevent cellular polyglutamine toxicity caused by the Huntington’s disease mutation. J. Biol. Chem. 2002; 277:33791–33798.
23. Berger Z, Ttofi EK, Michel CH, et al. Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway. Hum Mol Genet 2005; 14:3003-11.
24. S Sarkar, RA Floto and Z Berger, et al. Lithium induces autophagy by inhibiting inositol monophosphatase, J Cell Biol . 2005; 170:1101–1111.
25. Sovan SD, Rubinsztein C. Inositol and IP3 Levels Regulate Autophagy. Autophagy2006; 2:2, 132-134.
26. Sarkar S, Perlstein EO, Imarisio S, et al. Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat. Chem. Biol. 2007; 3:331–338.
27.Mizushima N, Levine B, Cuervo AM, et al. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069-75.
28. Fimia GM, Stoykova A, Romagnoli A, et al. Ambra1 regulates autophagy and development of the nervous system. Nature. 2007;447:1121-5.
29. Pandey UB, Nie Z, Batlevi Y, et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 2007;447:859-63.
30. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441:880-4.
31. Hara T, Nakamura K, Matsui M, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441:885-9.
32. Levine B, Kroemer G.. Autophagy in the pathogenesis of disease. Cell. 2008;132:27-42.
33. Komatsu M, Waguri S, Koike M, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131:1149-63.
34. Rubinsztein DC, Gestwicki JE, Murphy LO, et al. Potential therapeutic applications of autophagy. Nat Rev Drug Discov. 2007;6:304-12.
1. Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation period. Nature 2004; 432:1032–1036
2. Anglade P, Vyas S, Javoy-Agid F, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol. Histopathol.1997; 12(1):25–31
3. Stefanis L, Larsen KE, Rideout HJ, et al. Expression of A53T mutant but not wild-type a-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation, loss of dopamine release, and autophagic cell death. Neurosci. 2001; 21: 9549–9560
4. Spillantini M, Schmidt M, Trojanowski J, et al. a-synuclein in Lewy bodies. Nature1999; 388:839-840
5. Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusionbody formation in a-synuclein mice: Implications for neurodenerative disorders. Science; 2000; 287(5456):1265-1269
6. Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000; 290(5493): 985-989
7.钱进军,程言博,刘春风,杨亚萍,刘康永.人SNCA基因真核表达载体的构建及其在PC12细胞中的表达.细胞与分子免疫学杂志. 2008; 24(1): 23-26.
8. Kruger R, Kuhn W, Muller T, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet. 1998; 18:106-108
9.Charleen TC. Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 2006; 65:423-432.
10.Tanida I, Minematsu-Ikeguchi N, Ueno T, Kominami E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy. 2005;1:84-91
11.Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013
12.Shao Y, Gao Z, Marks PA ,et al. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A. 2004; 101(52): 18030-5.
13.Furuya N, Liang XH, and LevineB. 2004. Autophagy and cancer. In autophagy.D.J. Klionsky,editor. Landes Bioscience.Georgetown,Texas,USA.244-253
14. Fujiwara H, Hasegawa M, Dohmae N, et al. ?a-synuclein is phosphorylated in synucleinopathies. Nat cell Biol, 2002; 4: 160-164
15. Hsu LJ, Sagara Y, Arroyo A, et al. alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 2000; 157: 404-410
16. Lotharis J, Barg S, Wiekop P, et al. Effect of a-synuclein on dopamine homeostasis in a new human mesencephalic line. Biol Chem. 2002; 277:38884-38894
17. Dalfo’E, Gomez-Isla T, Rosa JL, et al. Abnormal a-synuclein interactions with Rat proteins in a-synuclein A30P transgenic mice. Neuropathol Exp Neurol, 2004; 63: 302-313
18. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress inneurodegenerative diseases. Nature. 2006; 443(7113): 787-795
19. Rojo AI, Montero C, Salazar M, et al. Persistent penetration of MPTP through the nasal route induces Parkinson's disease in mice. Euro Neurosci 2006; 24:1874-1884
20.Michel PP, Alvarez-Fischer D, Guerreiro S, et al. Role of activity-dependent mechanisms in the control of dopaminergic neuron survival. Neurochem 2007; 101: 289-297
21. Turnbull S, Tabner BJ, El-Agbaf OM, et al. alpha-Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med.2001; 30(10):1163-1170
22. Lovell MA, Xiong S, Xie C, et al. Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. Alzheimers Dis.2004; 6: 659-671.
23. Petrucelli L, Dawson TM. Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system. Ann Med 2004;36:315–320.
24. Song DD, Shults CW, Sisk A, et al. Enhanced substantia nigra mitochondrial pathology in human [alpha]-synuclein transgenic mice after treatment with MPTP. Exp. Neurol. 2004; 186: 158-172
25. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290:1717–1721.
26. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
27. Shimizu S, Kanaseki T, Mizushima N. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004; 6(12): 1221-8.
28. Mizushima N, Sugita H, Yoshimori T, et al. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem. 1998; 273(51): 33889-92.
29. Kanzama T, Zhang L, Xiao L, et al. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3 Oncogene. 2005; 24: 980-991
30. Li Yu, Fengyi Wan,Sudeshna,Dutta, et al. Autophagic programmed cell death by selective catalase degradation. PNAS 2006; 103: 4952-4957
31. Abeliovich H, Dunn WJ, Kim J, et al. Dissection of autophagosome biogenesis into distinct nucleation and expansion steps. Cell Biol. 2000; 151: 1025–1034.
32. Sovan S, Janet E D, Zebo H, et al. Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin andα-Synuclein. Biol. Chem., 2007; 282; 5641-5652.
33. Stefanis L, Larsen KE, Rideout HJ, et al. Expression of A53 T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 2001; 21:9549–9560
34. Chan L, Gaston R, Hariharan S. Evolution of immunosuppression and continued importance of acute rejection in renal transplantation. Am. J. Kidney Dis., 2001;38: 2–9.
35. Wellington CL, Singaraja R, Ellerby L, et al. Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. Biol. Chem., 2000; 275: 19831–9838
36. Beth L, Junying Y. Autophagy in cell death: an innocent convict? Clin Invest 2005; 115:2679-2688
37. Snyder H, Mensah K, Theisler H, et al. Aggregated monomeric alpha-synuclein bind to the 6S’proteasomal protein and inhibit proteasomal function. Biol Chem. 2003; 278(14): 11753-759
38. Tanaka Y, Engelender S, Igarashi et al. Inducible expression of mutant-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependant apoptosis. Hum Mol Genet. 2001; 10(9): 919-926
39.Thorburn Andrew. Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis.2008; 13(1):1-9
40. Iwamaru A, Kondo Y, Iwado E, et al. Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells. Oncogene.2007; 26(13):1840-1851
41.van der Vaart Aniek , Mari Muriel, Reggiori Fulvio. A Picky Eater: Exploring the Mechanisms of Selective Autophagy in Human Pathologies.Traffic 2008; 9(3):281-289
42. Ravikumar Brinda, Stewart Abigail, Kita Hiroko, et al. Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy.Human Molecular Genetics.2003;12(9):985-994
1. Spillantini M, Schmidt M, Trojanowski J, et al.α-synuclein in Lewy bodies.Nature1999; 388:839-840
2. Anglade P, Vyas S, Javoy-Agid F,et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol. Histopathol.1997; 12(1):25–31
3. Stefanis L, Larsen KE, Rideout HJ, et al. Expression of A53T mutant but not wild-typeα-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation, loss of dopamine release, and autophagic cell death. Neurosci. 2001; 21: 9549–9560
4.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志. 2008; 41(1): 51-56
5.Yang YP, Liu KY, Qian JJ, et al. The abnormal aggregation of alpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007 ; 14 (Suppl. 1):197
6. Charleen TC. Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 2006; 65:423-432.
7.Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013
8.Shao Y, Gao Z, Marks PA, et al. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A. 2004; 101(52): 18030-5.
9.Furuya N, Liang XH, and Levine B. 2004. Autophagy and cancer. In autophagy.D.J. Klionsky,editor. Landes Bioscience.Georgetown,Texas,USA.244-253
10.Beyer K. a-Synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol 2006; 112: 237–251.
11. Marta Martinez-Vicente, Ana Maria Cuervo. Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 2007; 6: 352–61.
12. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006; 441(7095): 880-884.
13. Noboru Mizushima1. Autophagy: process and function. Genes & Dev. 2007; 21: 2861-2873
14.Beth Levine and Guido Kroemer. Autophagy in the Pathogenesis of Disease. Cell.2008;132:28-42.
15. Lotharis J, Barg S, Wiekop P, et al. Effect ofα-synuclein on dopamine homeostasis in a new human mesencephalic line. Biol Chem, 2002; 277:38884-38894
16. Dalfo’E, Gomez-Isla T, Rosa JL, et al. Abnormalα-synuclein interactions with Rat proteins inα-synuclein A30P transgenic mice. Neuropathol Exp Neurol, 2004; 63: 302-313
17. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443(7113): 787-795
18.Turnbull S, Tabner BJ, El-Agbaf OM, et al. alpha-Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med.2001; 30(10):1163-1170
19. Rojo AI, Montero C, Salazar M, et al. Persistent penetration of MPTP through the nasal route induces Parkinson's disease in mice. Euro Neurosci 2006; 24:1874-1884
20.Michel PP, Alvarez-Fischer D, Guerreiro S, et al. Role of activity-dependent mechanisms in the control of dopaminergic neuron survival. Neurochem 2007; 101: 289-297
21. Lehmensiek V, Tan EM, Schwarz J, et al. Expression of mutant alpha-synucleins enhances dopamine transporter-mediated MPP+ toxicity in vitro. Neuroreport.2002; 13:1279–1283.
22. . Rojo AI, Montero C, Salazar M, et al. Persistent penetration of MPTP through the nasal route induces Parkinson's disease in mice. Euro Neurosci 2006; 24:1874-1884
23. Petrucelli L, Dawson TM. Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system. Ann Med 2004;36:315–320.
24.Qian JJ, Cheng YB,Yang YP, Mao CJ, Qin ZH, Li K, Liu CF. Differential effects of overexpression of wild-type and mutant humanα-synuclein on MPP+-induced neurotoxicity in PC12 cells. Neurosci Lett. (Acceptted , DOI information: 10.1016/j.neulet.2008.02.021).
25. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
26. Shimizu S, Kanaseki T, Mizushima N. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004; 6(12): 1221-8.
27. Kanzama T, Zhang L,Xiao L, et al. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3 Oncogene. 2005; 24: 980-991
28. Li Yu, Fengyi Wan, SudeshnaDutta, et al. Autophagic programmed cell death by selective catalase degradation. PNAS 2006; 103: 4952-4957
29. ?sa B. Gustafsson, Roberta A. Gottlieb.The role of autophagy in cardioprotection. YJMCC-06240; No. of pages: 8; 4C: 2 .2008.
30. Lovell MA, Xiong S, Xie C, et al. Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. Alzheimers Dis.2004; 6: 659-671.
31. Song DD, Shults CW, Sisk A, et al. Enhanced substantia nigra mitochondrial pathology in human [alpha]-synuclein transgenic mice after treatment with MPTP. Exp. Neurol. 2004; 186: 158-172
32.Beyer K. a-Synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol 2006; 112: 237–251.
33. Koichi Wakabayashi, Kunikazu Tanji, Fumiaki Mori1 and Hitoshi Takahashi.The Lewy body in Parkinson’s disease: Molecules implicated in the formation and degradation of a-synuclein aggregates. Neuropathology 2007; 27, 494–506.
34. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 1997;22:267-72
35.Tassa A, Roux MP, Attaix D, Bechet DM. Class III phosphoinositide 3-kinase-Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem J 2003;376:577-86
36. Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P. Distinct classes of phosphatidylinositol 3-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 2000;275:992-98
37 Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005, 120(2): 237-248.
38.Sophie Pattingre, Lucile Espert, Martine Biard-Piechaczyk, et al. Regulation ofmacroautophagy by mTOR and Beclin 1 complexes. Biochimie 90 (2008) 313-323.
39.Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell, 2004; 6(4): 463-477.
40. Uttenweiler A, Schwarz H, Neumann H, et al. The vacuolar transporter chaperone (VTC) complex is required for microautophagy. Mol. Biol. Cell, 2007; 18(1): 166 - 175.
41.Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol, 2005; 169(3): 425-434.
42. Rubinsztein DC, Gestwicki JE; Murphy LO, and Klionsky DJ. Potential therapeutic applications of autophagy. Nat. Rev. Drug Discov. 2007;6:304–312.
43.Sovan S, Janet ED, Zebo H,et al. Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin andα-Synuclein. Biol. Chem., 2007; 282; 5641-5652.
44. Zhu J-H, Kulich SM, Oury TD, Chu CT. Cytoplasmic aggregates of phosphorylated extracellular signal-regulated kinase in Lewy body diseases. Am J Pathol 2002;161:2087-98
45. Chu CT, Levinthal DJ, Kulich SM, Chalovich EM, DeFranco DB. Oxidative neuronal injury. The dark side of ERK1/2. Eur J Bichem 2004;271:2060-66
46. Rodriguez-Enriquez S, Kim I, Currin RT, Lemasters JJ. Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy 2006;2:39-46
47. Zahniser N.R. and Doolen S. Chronic and acute regulation of Na+/Cl- -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther, 2001; 92(1):21-55.
48.Wersinger C. and Sidhu A. Attenuation of dopamine transporter activity by alpha-synuclein. Neurosci Lett, 2003; 340(3):189-192.
49.Wersinger C; Prou D; Vernier P; et al. Modulation of dopamine transporter function by alpha-synuclein is altered by impairment of cell adhesion and by induction of oxidative stress. Faseb J, 2003; 17(14):2151-2153.
1.Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000; 290(5493): 985-989
2. Polymeropoulos MH. Autosomal dominant Parkinson's disease and alpha-synuclein. Ann Neurol 1998; 44:S63–S64.
3.Stefanis L, Larsen KE, Rideout HJ, et al. Expression of A53 T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 2001; 21:9549–9560.
4.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志. 2008; 41(1): 51-56
5.Yang YP, Liu KY, Qian JJ, et al. The abnormal aggregation of alpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007; 14 (Suppl. 1):197
6. Anglade P, Vyas S, Javoy-Agid F,et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol. Histopathol.1997; 12(1):25–31
7. Hoffman BJ, Hansson SR, Mezey E, et al. Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Front Neuroendocrinol,1998;19(3):187-231
8. Liu YJ, Robert HE. The role of vesicular transport proteins in synaptic transmission and neural degeneration. Anns Neurosci. 1997; 20:125-156
9.Uhl GR. Hypothesis: The role of dopaminergic transporters in selectivevulnerability of cell in Parkinson’s disease. Ann Neurology.1998; 43(5):555-560
10.Kitayama S, Wang JB, Uhl GR. Dopamine transporter mutants selectively enhance MPP+ transport. Synapse.1993; 15(1):58-62
11.Liu Y, Peter D, Roghani A, et al. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell. 1992;70(4):539-551
12.Trimbele WS, Linial M, Scheller RH. Cellular and molecular biology of the presynaptic nerve terminal. Annu Rev Neurosci.1991; 14:93-122
13.Brooks DJ, Frey KA, Marek KL, et al. Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease. Exp Neurol, 2003, 184 Suppl 1:S68-79.
14.Choi HJ, Lee SY, Cho Y, et al. Inhibition of vesicular monoamine transporter enhances vulnerability of dopaminergic cells: relevance to Parkinson's disease. Neurochem Int, 2005; 46(4):329-335.
15. German DC, Liang CL, Manaye KF, et al. Pharmacological inactivation of the vesicular monoamine transporter can enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of midbrain dopaminergic neurons, but not locus coeruleus noradrenergic neurons. Neuroscience, 2000; 101(4):1063-1069.
16. Liu Y. and Edwards RH. The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annu Rev Neurosci, 1997; 20:125-156.
17.Liang CL, Nelson O, Yazdani U, et al. Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: human midbrain dopamine neurons. J Comp Neurol, 2004, 473(1):97-106.
18.Sanghera MK, Manaye K, McMahon A, et al. Dopamine transporter mRNA levels are high in midbrain neurons vulnerable to MPTP. Neuroreport. 1997; 8(15):3327-3331.
19.Storch1 A, Ludolph1 AC, and Schwarz J. Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration .J Neural Transm 2004;111: 1267–1286
20.Won Yong Lee, Eun Ah Lee, Mi Young Jeon, et al. Vesicular monoaminetransporter-2 and aromatic L-amino acid decarboxylase gene therapy prevents development of motor complications in parkinsonian rats after chronic intermittent L-3,4-dihydroxyphenylalanine administration Experimental Neurology 2006; 197:215-224
21.Won Yong Lee, Jin Woo Chang, Nicole L, et al. Vesicular Monoamine Transporter-2 and Aromatic L-Amino Acid Decarboxylase Enhance Dopamine Delivery after L-3 , 4-Dihydroxyphenylalanine Administration in Parkinsonian Rats. Neuroscience. 1999; 19(8):3266-3274
22.Jannine G. Truong, Kristi S Rau, Glen R Hanson, et al. Pramipexole increases vesicular dopamine uptake: implications for treatment of Parkinson's neurodegeneration. European Journal of Pharmacology 2003; 474: 223-226
23.Sun M, Kong L, Wang X, et al. Coexpression of tyrosine hydroxylase, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter 2 from a helper virus-free herpes simplex virus type 1 vector supports high-level, long-term biochemical and behavioral correction of a rat model of Parkinson's disease. Human Gene Therapy. 2004; 15(12):1177-96
24.Kumar MJ and Andersen JK. Perspectives on MAO-B in aging and neurological disease: where do we go from here? Mol Neurobiol, 2004; 30: 77-89
25.R.R. Gainetdinov, F. Fumagalli,Y.M. Wang, et al. Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice. Neurochem1998; 70: 1973–1978.
26.D.C. German; C.L. Liang; K.F. Manaye; K. Lane and P.K. Sonsalla, Pharmacological inactivation of the vesicular monoamine transporter can enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of midbrain dopaminergic neurons, but not locus coeruleus noradrenergic neurons, Neuroscience 2000; 101: 1063–1069.
27.J.G. Nutt. Long-term L-DOPA therapy: challenges to our understanding and for the care of people with Parkinson's disease, Exp. Neurol. 2003; 184:. 9–13
28.J.G. Nutt, J.H. Carter, E.S. Lea et al. Evolution of the response to levodopa during the first 4 years of therapy, Ann. Neurol. 2002; 51: 686–693.
29.R.G. Staal and P.K. Sonsalla, Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata, J. Pharmacol. Exp. Ther. 2000; 293: 336–342.
30.Carlsson C,Winkler C, Burger N, Muzyczka R.J, Mandel A. Cenci and A. Kirik, Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors, Brain 2005; 128:. 559–569.
31.Moszczynska A, Saleh J, Zhang H, et al. Parkin Disrupts theα-Synuclein/Dopamine Transporter Interaction: Consequences Toward Dopamine-induced Toxicity. Journal of Molecular Neuroscience. 32(3):217-227, July 2007.
32. Chen MK, Kuwabara H, Zhou Y, et al. VMAT2 and dopamine neuron loss in a primate model of Parkinson's disease. Journal of Neurochemistry. 105(1):78-90, April 2008.
33. Spillantini M, Schmidt M, Trojanowski J, et al.α-synuclein in Lewy bodies. Nature1999; 388:839-840
34. Fujiwara H, Hasegawa M, Dohmae N, et al. ?α-synuclein is phosphorylated in synucleinopathies. Nat cell Biol, 2002; 4: 160-164
35. Hsu LJ, Sagara Y, Arroyo A, et al. alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol, 2000; 157: 404-410
36. Petrucelli L, Dawson TM. Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system. Ann Med 2004; 36:315–320.
37. Song DD, Shults CW, Sisk A, et al. Enhanced substantia nigra mitochondrial pathology in human [alpha]-synuclein transgenic mice after treatment with MPTP. Exp. Neurol. 2004; 186: 158-172
38.Lee FJ, Liu F, Pristupa ZB, Niznik HB. Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. Faseb J 2001;15:916-26
39.Gomez-Santos C, Ferrer I, Santidrian AF, Barrachina M, Gil J, Ambrosio S. Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. J Neurosci Res 2003;73:341-50
40.Sulzer D, Bogulavsky J, Larsen KE, et al. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci U S A 2000;97:11869-74
41. Mizushima N, Sugita H, Yoshimori T, et al. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy.J Biol Chem. 1998; 273(51): 33889-92.
42. Abeliovich H, Dunn WJ, Kim J, et al. Dissection of autophagosome biogenesis into distinct nucleation and expansion steps. Cell Biol. 2000; 151: 1025–1034.
43. Sovan S, Janet ED, Zebo H, et al. Trehalose, a Novel mTOR-independent Autophagy Enhancer , Accelerates the Clearance of Mutant Huntingtin andα-Synuclein. Biol. Chem. 2007; 282; 5641-5652.
44. Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013
45. Huang WP and Klionsky DJ. Autophagy in yeast: a review of the molecular machinery. Cell Struct Funct 2002; 27:409–420.
46. Klionsky DJ and Ohsumi Y. Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol 1999; 15:1–32.
47. Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 2001; 152:657–668.
48. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290:1717–1721.
49. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
50. Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M and Ohzumi Y. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 2000; 150:1507–1513.
51. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
52. Ohsawa Y, Isahara K, Kanamori S, Shibata M, Kametaka S, Gotow T, et al. An ultrastructural and immunohistochemical study of PC12 cells during apoptosis induced by serum deprivation with special reference to autophagy and lysosomal cathepsins. Arch Histol Cytol 1998; 61:395–403.
53. Levine B and Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6:463–477.
54. Shimizu S, Kanaseki T, Mizushima N, et al. Role of Bcl-2 family proteins in a 2004; 6(12): 1221-8.
55. Kanzama T, Zhang L, Xiao L, et al. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3 Oncogene. 2005; 24: 980-991
56.Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013.
57. Chan L, Gaston R, Hariharan S. Evolution of immunosuppression and continued importance of acute rejection in renal transplantation. Am. J. Kidney Dis., 2001;38: 2–9.
58. Wellington CL, Singaraja R, Ellerby L, et al. Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. Biol. Chem., 2000; 275: 19831–9838
1. Moore DJ, West AB,st, Dawson VL: Molecular pathophysiology of Parkinson’s disease. Annu. Rev. Neurosci. 2005, 28: 57-87
2. Cookson MR, Brug MV, Cell system and the toxic mechanism(s) ofα-synuclein. Experimental Neurology, 2008,209: 5-11
3. Liu H, Wang XZ, Alpha-synuclein and Parkinson disease. Neural Regen Res, 2007, 2: 39-43
4. Li HT., Du HN, Tang L, et al. Structural transformation and aggregation of human alpha-synuclein in trifluoroethanol: non-amyloid component sequence is essential and beta-sheet formation is prerequisite to aggregation, Biopolymers, 2002,64: 221-226
5. Zarranz JJ, Lezcano E, Alegre J, et al. The new mutation, E46K, ofα-synuclein causes Parkinson and Lewy Body Dementia. Ann Neurol 2004,55: 164-173
6. Winkler S, Hagenah J, Klein C, et al.α-Synuclein and Parkinson disease susceptibility. Neuology, 2007,69: 1345-50
7. Parsian AJ, Patra B, Parsian A, et al. Association ofα-synuclein gene haplotypes with Parkinson’s disease. Parkinsonism and Related Disorders,2007,13:343-47
8. Maraganore DM, Andrade MD, Farrer MJ, et al. Collaorative analysis ofα-synuclein gene promoter variability and Parkinson disease. JAMA 2006;96: 661-670
9.何延波,陈彪.α-synuclein基因多态性与帕金森病.中华神经科杂志.2007;2:133-135
10. Crowther RA, Daniel SE, Goedert M, Characteristerisation of isolated alpha-synuclein filaments from substantia nigra of Parkinson’s disease brain, Neurosci. Lett., 2000;92: 128-130
11. Miake H, Mizusawa H, Iwatsubo T, et al. Biochemical characterization of the core structure of alpha-synuclein filaments. Biol. Chem. 2002;277: 19213-19219
12. Zhang F, Lin XJ, Hu HY, et al. Assembly ofα-synuclein fibrils in nanoscale studied by peptide truncation and AFM. Biochemical and Biophysical Research Communications. 2008;368: 388-394
13. Hoyer W, Cherny D, Subramaniam V, et al. Rapid self-assembly of alpha-synuclein observed by in situ atomic force microscopy, J. Mol. Biol., 2004,340: 127-139
14. Kim M, Jung W, Hahn JS, et al. Impairment of microtubule system increasesα-synuclein aggregation and toxicity. Biochemical and Biophysical Research Communications. 2008;365: 628-635
15. Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003;300: 636-640
16. Lindersson E, Lundvig D, Petersen C, et al. p25alpha stimulates alpha-synuclein aggregation and is colocalized with aggregated alpha-synuclein in alpha-synucleinopathies, J. Biol. Chem. 2005,280: 5703-5715
17. Chen MK, Kuwabara H, Zhou,Y, et al. VMT2 and dopamine neuron loss in a primate model of Parkinson’s disease. Journal of Neurochemistry. 2008; 105(1): 78-90
18. Liu CW, Giasson BI, Thomas PJ, et al. A precipitating role for Truncatedα-synuclein and Proteasome inα-synuclein Aggregation.Biol.Chem.2005;280: 22670-22678
19. Kasai T, Tokuda T, Mizuno T, et al. Cleavage of nomal and pathological forms ofα-synuclein by neurosin in vitro, Neurosci. Lett. (2008), doi: 10.10.16/j. neulet 2008 02. 057
20. Dufty BM, Wamer LR, Rohn TT, et al. Calpain-cleavage ofα-synuclein. The American Journal of Pathology. 2007;170: 1725-1738
21. Iwatsubo T , Pathological biochemistry ofα-syncleinopathy , Neuropathology 2007,27: 474-478
22. Kim HY, Heise H, Fernandez CO, et al. correlation of amyloid fibril beta-structure with the unfolded state of alpha-synuclein, Chembiochem, 2007, 8: 1671-1674
23. Bharathi, Indi SS, Rao KSJ: Copper- and iron-induced differential fibril formation inα-synclein: TEM study. Neuroscience Letters. 2007: 424: 78-82
24. Bharathi and Rao KSJ: Thermodynamics imprinting reveals differential binding of metals toα-synuclein: Relevance to Parkinson’s disease. Biochemical and biophysical research communications. 2007;359: 115-120.
25. Giannakis E, Pacifico J, Smith DP, et al. Dimeric structures ofα-synuclein bind preferentially to lipid membranes. Biochim. Biophys. Acta. 2008;1778: 1112-1119
26. Danzer KM, Haasen D, Anne R, et al. Different species ofα-synuclein oligomers induce calcium influx and seeding. The Journal of Neuroscience. 2007;27: 9220-9232
27. Demuro A, Parker I, Glabe CG, et al. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. Biol. Chem. 2005; 280: 17294-17300
28. Lashuel HA, Lansbury PT Jr. Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins? Q. Rev. Biophys 2006; 39: 167-201
29. Green JD, Kreplak L, Goldsbury C, et al. Atomic force reveals defects within mica supported lipid bilayers induced by the amyloidogenic human amylin peptide. Biol Chem 2004; 342: 877-887
30. Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked toneurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000; 290(5493): 985-989
31. Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation inα-synuclein mice: Implications for neurodenerative disorders. Science; 2000; 287(5456):1265-1269
32. Tanaka Y , Engelender S , Igarashi et al. Inducible expression of mutant-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependant apoptosis. Hum Mol Genet. 2001; 10(9): 919-926
33. Tashiro M, Kojima M, Kihara H, et al., Characterization of fibrillation process ofα-synuclein at the initial stage. Biochem. Biophys. Res. Commun., 2008,369: 910-914
34. Kamiyoshihara T, Kojima M, Uéda K, et al. Observation of multiple intermediates inα-synuclein fibril formation by singular value decomposition analysis, Biochem. Biophys. Res. Commun. 2007,355: 398-403
35. Senior SL, Ninkina N, Deacon R, et al. Increased striatal dopamine release and hyperdopaminergic-like bahaviour in mice lacking both alpha-synuclein and gamma-synuclein. European Journal of Neuroscience. 2008; 27(4): 947-957
36. Moszczynska A, Saleh J, Zhang HY, et al. Parkin disrupts the alpha synuclein/Dopamine Transporter Interaction: Consequences Toward Dopamine-induced Toxicity. Journal of Molecular Neuroscience. 2007; 32(3):217-227
37. Li W, Lesuissem C, Xu Y, et al. Stabilization of alpha-synuclein protein with aging and familial Parkkinson’s disease-linked A53T mutation. Neurosci. 2004;24:7400-7409.
38. Clough RL, Stefanis L, A novel pathway for transcripitional regulation ofα-synuclein. The FASEB Journal, 2007,21: 596-607
39. Gomez-Santos C., Barrachina M., Gimenez-Xavier P., et al., Induction of C/EBP beta and GADD153 expression by dopamine in human neuroblastoma cells. Relationship with alpha-synuclein increases and cell damage. Brain Res. Bull., 2005; 65: 87-95
40.Chiba-Falek O, Kowalak JA, Smulson ME, et al. Regulation ofα-synucleinexpression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of SNCA gene. American Journal of Human Genetics, 2005; 76: 478-492
41. Spillantini M, Schmidt M, Trojanowski J, et al.α-synuclein in Lewy bodies. Nature1999; 388:839-840
42. Fuchs J, Nilsson C, Kachergus J, et al. Phenotypic variation in a large Swedish pedigree due to SNCA dupilication and triplication. Neurology. 2007;68: 916-922
43. Rubinsztein DC, The roles of intracellular protein-degradation pathways in neurodegeneration. Nature. 2006;443: 780-786
44. Berger Z, Ravikumar B, Rubinsztein DC, et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Human Molecular Genetics. 2006;15: 433-442
45. Sarkar S, Davies J, Rubinsztein DC, et al. Trehalose, a noval mTOR-independent autophagy enhancer , accelerates the clearance of mutant huntingtin andα-synuclein. Biol.Chem. 2007;282: 5641-5652
46. Sarkar S, loto A, Rubinsztein DC, et al. Lithium induces autophagy by inhibiting inositol monophosphatase. The journal of cell biology. 2005;170: 1101-1111
47. Banhyopadhyay U, Cuervo AM, Chaperone-mediated autophagy in aging and neurodegeneration: Lessons fromα-synuclein. Experimental Gerontology. 2007;42: 120-128.
48. Shacka JJ, Roth KA, Zhang JH, The autophagy-lysosomal degradation pathway: role in neurodegenerative disease and therapy. Frontiers in Bioscience. 2008;13: 718-736
49. Pan TH, Kondo S, Le WD, et al. The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain. 2008; 1: 1-10
50. Yasuda T, Miyachi S, Y.Mizuno, Mochizuki H, et al. Neuronal specificity ofα-synclein toxicity and effect of Parkin co-expression in primates. Neuroscience. 2007;144: 743-53.
51. Martinez-Viceente M, Kaushik S, Massey AC, et al. Dopamine-modifiedα-synuclein blocks chaperone-mediated autophagy. Clin.Inves. doi:10.1172/JCI32806
52.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志.2008; 41(1): 51-56
53. Yang, YP, Liu KY, Qian JJ, et al. The abnormal aggregation of alpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007, 14 (Suppl. 1):197
54. Recchia A, Rota D, Debetto P, et al. Generation of aα-synclein-based rat model of Parkinson’s disease. Neurobiology of Disease.2008;30: 8-18.
55. Wakamatsu M, Ishii A, Iwata S, et al. Selective loss of nigral dopamine neurons induced by overexpression of truncated humanα-synclein in mice. Neurobiology of Aging. 2008; 29: 574-85.
56. Eslamboli A, Baker H, Ridley RM, et al. Long-term conseauences of human alpha-synuclein overexpression in the primate ventral midbrain. Brain.2007;130: 799-815
1. Shintani T, Klionky DJ. Autophagy in health and disease: a double-edged sword. Science, 2004, 306: 990-995.
2. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell, 2004, 6(4): 463-477.
3. Rubinsztein DC, DiFiglia M, Heintz N, et al. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy. 2005, 1(1): 11-22.
4. Noboru Mizushima1. Autophagy: process and function. Genes & Dev. 2007. 21: 2861-2873.
5. Noda T, Suzuki K, Ohsumi Y. Yeast autophagosomes: de novo formation of a membrane structure. Trends Cell Biol, 2002, 12(5): 231-235.
6. Dunn WA Jr. Studies on the mechanisms of autophagy: formation of the autophagic vacuole. J Cell Biol, 1990, 110(6): 1923-1933.
7. Yamamoto A, Masaki R, Tashiro Y, et al. Characterization of the isolation membranes and the limiting membranes of autophagosomes in rat hepatocytes by lectin cytochemistry. J Histochem Cytochem, 1990, 38(4): 573-580.
8. Mizushima N, Noda T, Yoshimori T, et al. A protein conjugation system essential for autophagy. Nature, 1998, 395(6700): 395-398.
9. Mizushima, N., and Klionsky, D. (2007). Protein turnover via autophagy: implications for metabolism. Annu. Rev. Nutr. 27, 19–40.
10. Kirisako T, Baba M, Ishihara N, et al. Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol, 1999, 147(2): 435-446.
11. Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005, 120(2): 237-248.
12. Cardenas ME, Cutler NS, Lorenz MC, et al. The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev, 1999, 13(24): 3271-3279.
13. Sophie Pattingre, Lucile Espert, Martine Biard-Piechaczyk , et al. Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie 90 (2008) 313-323.
14. Uttenweiler A, Schwarz H, Neumann H, et al. The vacuolar transporter chaperone (VTC) complex is required for microautophagy. Mol. Biol. Cell, 2007; 18(1): 166 - 175.
15. Beth Levine and Guido Kroemer. Autophagy in the pathogenesis of disease. Cell.132:28-42. 2008.
16. Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol, 2005, 169(3): 425-434.
17. Rubinsztein, D.C., Gestwicki, J.E., Murphy, et al. (2007). Potential therapeutic applications of autophagy. Nat. Rev. Drug Discov. 6, 304–312.
18. R Kiffin, C Christian, E Knecht, et al. Activation of chaperone-mediated autophagy during oxidative stress, Mol Biol Cell 15 (2004), 4829–4840.
19. Kaushik S, Massey AC, Mizushima N, et al. Constitutive Activation of Chaperone-mediated Autophagy in Cells with Impaired Macroautophagy. Mol Biol Cell. 2008 Mar 12 [Epub ahead of print].
20. Charleen T. Chu, MD, PhD. Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 2006; 65:423-432.
21. Gustafsson ?B, Gottlieb RA. Recycle or die: The role of autophagy in cardioprotection, J Mol Cell Cardiol (2008).1-8.
22. Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl), 1990, 181(3): 195-213.
23. AM Cuervo, E Bergamini, UT Brunk, et al. Autophagy and aging: the importance of maintaining“clean”cells, Autophagy 1 (2005), 131–140.
24. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 2006, 441(7095): 880-884.
25. Stefanis L. Caspase-dependent and -independent neuronal death: two distinct pathways to neuronal injury. Neuroscientist, 2005, 11(1): 50-62.
26. Lockshin RA, Zakeri Z. Apoptosis, autophagy, and more. Int J Biochem Cell Biol, 2004, 36(12): 2405-2419.
27. Pyo JO, Jang MH, Kwon YK, et al. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem, 2005, 280(21): 20722-20729.
28. Maiuri, M.C., Zalckvar, E., Kimchi, A., et al. (2007). Self-eating andself-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 8, 741–752.
29. Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest, 2005, 115(10): 2679-2688.
30. Hara T, Nakamura K, Matsui M. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice, 2006, 441(7095): 885-889.
31. Beyer K. a-Synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol 2006; 112: 237–251.
32. Marta Martinez-Vicente , Ana Maria Cuervo. Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 2007; 6: 352–61.
33. Nakai, A., Yamaguchi, O., Takeda, T., et al. 2007. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat.Med. 13: 619–624.
34. Koichi Wakabayashi, Kunikazu Tanji, Fumiaki Mori1 et al. The Lewy body in Parkinson’s disease: Molecules implicated in the formation and degradation of a-synuclein aggregates. Neuropathology 2007; 27, 494–506.
35.Yu WH, Cuervo AM, Kumar A, et al. Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol, 2005, 171(1): 87-98.
36 Nixon RA, Wegiel J, Kumar A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol, 2005, 64(2): 113-122.
37. Glabe C. Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J Mol Neurosci 2001, 17(2): 137-145.
38. Qin ZH,Wang Y,Kegel KB,et al. Autophagy regulates the processing of amino terminal huntingtin fragments. Hum Mol Genet, 2003, 12(24): 3231-3244.
39. Huang WP and Klionsky DJ. Autophagy in yeast: a review of the molecular machinery. Cell Struct Funct 2002; 27:409–420.
40. AM Cuervo, L Stefanis, R Fredenburg, et al. Impaired degradation ofmutant alpha-synuclein by chaperone-mediated autophagy, Science 305 (2004), 1292–1295.
41. Klionsky DJ and Ohsumi Y. Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol 1999; 15:1–32.
42. Mizushima N , Yamamoto A , Hatano M , et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 2001; 152:657–668.
43. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290:1717–1721.
44.AC Massey, S Kaushik, G Sovak, R Kiffin and AM Cuervo, Consequences of the selective blockage of chaperone-mediated autophagy, Proc Natl Acad Sci USA 103 (2006), 5805–5810.
45. AIwata, BE Riley, JA Johnston and RR Kopito, HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin, J Biol Chem 280 (2005), 40282–40292.
46. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
47. Kamada Y, Funakoshi T, Shintani T, et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 2000; 150:1507–1513.
48. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304:1500–1502.
49. Ohsawa Y, Isahara K, Kanamori S, et al. An ultrastructural and immunohistochemical study of PC12 cells during apoptosis induced by serum deprivation with special reference to autophagy and lysosomal cathepsins. Arch Histol Cytol 1998; 61:395–403.
50.Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278:25009–25013.
51.刘康永,刘春风,钱进军,等.突变型α-synuclein的自噬性降解途径及可能机制.中华神经科杂志, 2008, 41(1): 51-56.
52.Yang, YP, Liu KY, Qian JJ, et al. The abnormal aggregation ofalpha-synuclein induces autophagic programmed cell death in PC12 cells. Eur J Neurol. 2007, 14 (Suppl. 1):197.
53. Rott R, Szargel R, Haskin J, Shani V, Shainskaya A, Manov I, Liani E, Avraham E, Engelender S. Monoubiquitination ofα-synuclein by SIAH promotes its aggregation in dopaminergic cells. J Biol Chem 2007.
54. Simone Engelender. Ubiquitination ofα-synuclein and autophagy in Parkinson’s disease. Autophagy 4:3, 1-3, 2008.
55. Nonaka T, Iwatsubo T, Hasegawa M. Ubiquitination ofα-synuclein. Biochemistry 2005; 44:36 -8.
56. Lee JT, Wheeler TC, Li L, Chin LS. Ubiquitination of {alpha}-synuclein by Siah promotesα-synuclein aggregation and apoptotic cell death. Hum Mol Genet 2007.
57. B Ravikumar, C Vacher and Z Berger et al., Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease, Nat Genet 36 (2004), 585–595.
58. Z Berger, B Ravikumar and FM Menzies et al., Rapamycin alleviates toxicity of different aggregate-prone proteins, Hum Mol Genet 15 (2006), 433–442.
59. Carmichael, J., K.L. Sugars, Y.P. Bao, and D.C. Rubinsztein. 2002. Glycogen synthase kinase-3 inhibitors prevent cellular polyglutamine toxicity caused by the Huntington’s disease mutation. J. Biol. Chem. 277:33791–33798.
60. Berger Z, Ttofi EK, Michel CH, et al. Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway. Hum Mol Genet 2005; 14:3003-11.
61. S Sarkar, RA Floto and Z Berger et al., Lithium induces autophagy by inhibiting inositol monophosphatase, J Cell Biol 170 (2005), 1101–1111.
62. Sovan Sarkar David C. Rubinsztein. Inositol and IP3 Levels Regulate Autophagy. Autophagy 2:2, 132-134, 2006.
63. Sarkar, S., Perlstein, E.O., Imarisio, S., et al. 2007. Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat. Chem. Biol. 3:331–338.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |