过表达人源E46K突变体α-synuclein对蛋白质降解系统的影响
摘要
帕金森病(Parkinson s disease, PD)是临床最常见的中枢神经系统退行性疾病之一,主要发生于中老年人群。在我国65岁以上人群发病率约为1.7%,发病人数超过200万。PD在病理学上主要表现为中脑黑质致密部多巴胺能神经元选择性丢失以及残存神经元胞体中有蛋白质包涵体被称为路易小体(Lewy Bodies, LBs)的出现。LBs的主要成分是α-突触核蛋白(α-synuclein, α-syn),由140个氨基酸残基组成。PD的发病机制目前尚未完全阐明,遗传学研究表明编码a-syn的基因点突变(包括A30P, A53T, E46K)及过表达与PD的发生有密切关系,但异常表达的α-syn的毒性机制仍不清楚。近年来研究表明α-syn异常表达与蛋白质降解系统功能异常密切相关。在本研究中,我们主要对过表达和E46K突变体α-syn对蛋白质降解系统的影响,其自身在细胞内的降解途径和降解速率以及对细胞的毒性进行研究。
一、过表达E46K突变体α-syn对蛋白质降解系统的影响
我们发现在PC12和HEK293细胞上稳定及瞬时过表达E46K突变体α-syn可显著抑制自噬底物蛋白p62的降解并促进其聚集。同时E46K突变体α-syn对p62的影响具有自噬依赖性。这些结果提示我们过表达E46K突变体α-syn损伤自噬功能。随后我们发现过表达E46K突变体α-syn对自噬的抑制作用发生在减少自噬吞噬体的形成而对溶酶体的功能没有显著影响。进一步机制研究发现,发现过表达E46K突变体α-syn可通过抑制c-Jun氨基末端激酶1(c-Jun N-terminal Kinase1, JNK1)的磷酸化导致Bcl-2磷酸化水平降低,同时增加自噬抑制性复合物Bcl-2/Beclinl的形成并降低自噬促进性复合物Beclinl/Vps34的形成,进而抑制自噬的发生。过表达E46K突变体α-syn对经典的哺乳动物雷帕霉素靶蛋白(the mammalian target of rapamycin, mTOR)介导的自噬调节信号通路无显著影响。我们还发现与E46K突变体α-syn不同,表达野生型(Wild type, WT) α-syn不影响细胞基础自噬和饥饿诱导的自噬。此外,过表达E46K突变体α-syn可抑制泛素蛋白酶体系统的功能并增强伴侣分子介导的自噬(Chaperone-med iated autophagy, CMA)水平。
二、E46K突变体α-syn在细胞内的降解途径
我们的研究发现,在PC12稳定株细胞中,E46K突变体α-syn主要通过蛋白酶体和大分子自噬途径所降解,WT α-syn主要通过蛋白酶体和伴侣分子介导的自噬(chaperon-mediated autophagy, CMA)途径所降解。此外,与WT蛋白相比,E46K突变体α-syn在PC12细胞内的降解速率显著降低。
三、过表达E46K突变体αsyn对细胞的毒性作用
我们的结果表明,稳定表达E46K突变体α-syn的PC12细胞表现为形态学的异常,包括形状变大和异常。在神经生长因子(Nerve Growth Factor, NGF)分化处理下,空载体组细胞出现完整的细胞突起,而转染E46K突变体α-syn的细胞对NGF的敏感性降低。此外,在分化的PC12细胞中,表达E46K突变体α-syn可增加细胞对鱼藤酮(Rotenone, Rot)刺激的敏感性,表现为细胞活力较空载体组细胞显著降低,凋亡率显著增加以及细胞内活性氧(Reactive Oxygen Species, ROS)水平显著升高。
综上所述,E46K突变体α-syn可抑制细胞的自噬功能,其机制可能通过抑制JNK1的磷酸化导致自噬吞噬体的形成减少。其次,E46K突变体α-syn可抑制UPS功能导致多聚泛素化蛋白的聚集并代偿性升高CMA活性。而过表达WTα-syn对细胞的自噬和UPS功能均无显著影响。此外,E46K突变体α-syn与WTα-syn在降解途径和降解速率上也有所不同,前者主要通过自噬和蛋白酶体途径降解,后者主要经蛋白酶体和CMA途径降解。与WT蛋白相比,E46K突变体α-syn在细胞内的降解速率显著降低。最后,过表达E46K突变体α-syn可增加细胞对Rot刺激的敏感性。
Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders, which mainly occurs in the aging group. Prevalence of PD for those aged over65years old is approximately1.7%in China, affecting more than200million people. PD is pathologically characterized by a prevalent loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain as well as the formation of intracytoplasmic proteinaceous deposits called Lewy Bodies (LBs) in the surviving neurons. The major component of LBs is a-synuclein (a-syn), a small protein comprised of140amino acids residues. The pathogenesis of PD remains obscure until recently. Genetic studies have revealed that three point mutations (including A30P, A53T and E46K) as well as multiplications of the entire gene locus in the gene encoding a-syn are associated with familial forms of PD; however, the pathological effects of aberrant forms of a-syn are still little known. Emerging publications have suggested a close relationship between a-syn and protein degradation system dysfunction. In this study, we mainly focused our attention on the effects of E46K mutant a-syn on protein degradation system. We also compared the degradation routes and rate between WT and E46K mutant a-syn. In addition we investigate the toxicity of E46K mutant a-syn on cells.
1. Effects of overexpression of E46K mutant a-syn on protein degradation system.
We discovered that both stable and transit overexpression of E46K mutant a-syn inhibited p62degradation and promoted p62aggregation in an autophagy-dependent manner, indicating impaired autophagy by E46K mutant a-syn. Next we found that overexpression of E46K mutant a-syn impaired autophagy at an early stage of autophagosome formation but not the lysosome degradation stage. Further studies suggested that E46K mutant a-syn inhibited autophagy via inactivation of c-Jun N-terminal Kinase1(JNK1). Levels of phosphorylated JNK1were significantly decreased by E46K. mutant a-syn followed by reduced phosphorylation of Bcl-2, which led to increased association between Bcl-2and Beclinl, further disrupting the formation of Beclinl/Vps34complex, a component essential to autophagy initiation. Meanwhile, we also discovered that E46K mutant a-syn impaired autophagy independently of classic mammalian target of rapamycin (mTOR)-mediated signal pathway. Meanwhile, in contrast to E46K mutant a-syn, overexpression of WT a-syn showed no influence in both basal and starvation-induced autophagy. Furthermore, overexpression of E46K mutant α-syn impaired ubiquitin-proteasome system (UPS) function and enhanced chaperone-mediated autophagy (CMA) activity.
2. Degradation pathways of E46K mutant α-synuclein
Our data showed that E46K mutant α-syn was mainly degraded by both proteasome and macroautophagy pathway in PC12cells and WT α-syn was turned over through proteasome and chaperon-mediated autophagy (CMA) pathway. Furthermore, compared with WT α-syn, E46K mutant α-syn turned over more slowly in PC12cells.
3. Overexpression of E46K mutant α-synuclein increases cell susceptibility to rotenone (Rot) insult.
Our data showed that PC12cells stable overexpression of E46K mutant α-synuclein displayed a number of morphological alterations such as increased size and aberrant appearance compared with vector control cells. After differentiated with nerve growth factor (NGF), PC12cells overexpressing GFP established a neuritic network. In contrast, cells overexpressing E46K mutant α-synuclein exhibited limited response to NGF treatment. In addition, overexpression of E46K mutant α-synuclein increased vulnerability of differentiated PC12cells to Rot treatment, exhibiting as decreased cell viability, increased apoptosis rates and augmented generation of reactive oxygen species (ROS).
In summary, we discovered that overexpressed E46K mutant α-syn inhibited autophagy initiation via inactivation of JNK1. Overexpressed E46K mutant α-syn led to impaired UPS function and compensatory elevation of CMA activity. In addition, E46K mutant α-syn was mainly degraded via proteasome and macroautophagy pathway while WT α-syn was cleared by proteasome and CMA pathway. Compared with WT protein, E46K mutant α-syn turned over more slowly. In addition, overexpression of E46K mutant α-synuclein increased vulnerability of differentiated PC12cells to Rot treatment.
一、过表达E46K突变体α-syn对蛋白质降解系统的影响
我们发现在PC12和HEK293细胞上稳定及瞬时过表达E46K突变体α-syn可显著抑制自噬底物蛋白p62的降解并促进其聚集。同时E46K突变体α-syn对p62的影响具有自噬依赖性。这些结果提示我们过表达E46K突变体α-syn损伤自噬功能。随后我们发现过表达E46K突变体α-syn对自噬的抑制作用发生在减少自噬吞噬体的形成而对溶酶体的功能没有显著影响。进一步机制研究发现,发现过表达E46K突变体α-syn可通过抑制c-Jun氨基末端激酶1(c-Jun N-terminal Kinase1, JNK1)的磷酸化导致Bcl-2磷酸化水平降低,同时增加自噬抑制性复合物Bcl-2/Beclinl的形成并降低自噬促进性复合物Beclinl/Vps34的形成,进而抑制自噬的发生。过表达E46K突变体α-syn对经典的哺乳动物雷帕霉素靶蛋白(the mammalian target of rapamycin, mTOR)介导的自噬调节信号通路无显著影响。我们还发现与E46K突变体α-syn不同,表达野生型(Wild type, WT) α-syn不影响细胞基础自噬和饥饿诱导的自噬。此外,过表达E46K突变体α-syn可抑制泛素蛋白酶体系统的功能并增强伴侣分子介导的自噬(Chaperone-med iated autophagy, CMA)水平。
二、E46K突变体α-syn在细胞内的降解途径
我们的研究发现,在PC12稳定株细胞中,E46K突变体α-syn主要通过蛋白酶体和大分子自噬途径所降解,WT α-syn主要通过蛋白酶体和伴侣分子介导的自噬(chaperon-mediated autophagy, CMA)途径所降解。此外,与WT蛋白相比,E46K突变体α-syn在PC12细胞内的降解速率显著降低。
三、过表达E46K突变体αsyn对细胞的毒性作用
我们的结果表明,稳定表达E46K突变体α-syn的PC12细胞表现为形态学的异常,包括形状变大和异常。在神经生长因子(Nerve Growth Factor, NGF)分化处理下,空载体组细胞出现完整的细胞突起,而转染E46K突变体α-syn的细胞对NGF的敏感性降低。此外,在分化的PC12细胞中,表达E46K突变体α-syn可增加细胞对鱼藤酮(Rotenone, Rot)刺激的敏感性,表现为细胞活力较空载体组细胞显著降低,凋亡率显著增加以及细胞内活性氧(Reactive Oxygen Species, ROS)水平显著升高。
综上所述,E46K突变体α-syn可抑制细胞的自噬功能,其机制可能通过抑制JNK1的磷酸化导致自噬吞噬体的形成减少。其次,E46K突变体α-syn可抑制UPS功能导致多聚泛素化蛋白的聚集并代偿性升高CMA活性。而过表达WTα-syn对细胞的自噬和UPS功能均无显著影响。此外,E46K突变体α-syn与WTα-syn在降解途径和降解速率上也有所不同,前者主要通过自噬和蛋白酶体途径降解,后者主要经蛋白酶体和CMA途径降解。与WT蛋白相比,E46K突变体α-syn在细胞内的降解速率显著降低。最后,过表达E46K突变体α-syn可增加细胞对Rot刺激的敏感性。
Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders, which mainly occurs in the aging group. Prevalence of PD for those aged over65years old is approximately1.7%in China, affecting more than200million people. PD is pathologically characterized by a prevalent loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain as well as the formation of intracytoplasmic proteinaceous deposits called Lewy Bodies (LBs) in the surviving neurons. The major component of LBs is a-synuclein (a-syn), a small protein comprised of140amino acids residues. The pathogenesis of PD remains obscure until recently. Genetic studies have revealed that three point mutations (including A30P, A53T and E46K) as well as multiplications of the entire gene locus in the gene encoding a-syn are associated with familial forms of PD; however, the pathological effects of aberrant forms of a-syn are still little known. Emerging publications have suggested a close relationship between a-syn and protein degradation system dysfunction. In this study, we mainly focused our attention on the effects of E46K mutant a-syn on protein degradation system. We also compared the degradation routes and rate between WT and E46K mutant a-syn. In addition we investigate the toxicity of E46K mutant a-syn on cells.
1. Effects of overexpression of E46K mutant a-syn on protein degradation system.
We discovered that both stable and transit overexpression of E46K mutant a-syn inhibited p62degradation and promoted p62aggregation in an autophagy-dependent manner, indicating impaired autophagy by E46K mutant a-syn. Next we found that overexpression of E46K mutant a-syn impaired autophagy at an early stage of autophagosome formation but not the lysosome degradation stage. Further studies suggested that E46K mutant a-syn inhibited autophagy via inactivation of c-Jun N-terminal Kinase1(JNK1). Levels of phosphorylated JNK1were significantly decreased by E46K. mutant a-syn followed by reduced phosphorylation of Bcl-2, which led to increased association between Bcl-2and Beclinl, further disrupting the formation of Beclinl/Vps34complex, a component essential to autophagy initiation. Meanwhile, we also discovered that E46K mutant a-syn impaired autophagy independently of classic mammalian target of rapamycin (mTOR)-mediated signal pathway. Meanwhile, in contrast to E46K mutant a-syn, overexpression of WT a-syn showed no influence in both basal and starvation-induced autophagy. Furthermore, overexpression of E46K mutant α-syn impaired ubiquitin-proteasome system (UPS) function and enhanced chaperone-mediated autophagy (CMA) activity.
2. Degradation pathways of E46K mutant α-synuclein
Our data showed that E46K mutant α-syn was mainly degraded by both proteasome and macroautophagy pathway in PC12cells and WT α-syn was turned over through proteasome and chaperon-mediated autophagy (CMA) pathway. Furthermore, compared with WT α-syn, E46K mutant α-syn turned over more slowly in PC12cells.
3. Overexpression of E46K mutant α-synuclein increases cell susceptibility to rotenone (Rot) insult.
Our data showed that PC12cells stable overexpression of E46K mutant α-synuclein displayed a number of morphological alterations such as increased size and aberrant appearance compared with vector control cells. After differentiated with nerve growth factor (NGF), PC12cells overexpressing GFP established a neuritic network. In contrast, cells overexpressing E46K mutant α-synuclein exhibited limited response to NGF treatment. In addition, overexpression of E46K mutant α-synuclein increased vulnerability of differentiated PC12cells to Rot treatment, exhibiting as decreased cell viability, increased apoptosis rates and augmented generation of reactive oxygen species (ROS).
In summary, we discovered that overexpressed E46K mutant α-syn inhibited autophagy initiation via inactivation of JNK1. Overexpressed E46K mutant α-syn led to impaired UPS function and compensatory elevation of CMA activity. In addition, E46K mutant α-syn was mainly degraded via proteasome and macroautophagy pathway while WT α-syn was cleared by proteasome and CMA pathway. Compared with WT protein, E46K mutant α-syn turned over more slowly. In addition, overexpression of E46K mutant α-synuclein increased vulnerability of differentiated PC12cells to Rot treatment.
引文
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