建立果蝇模型研究人类泛酸激酶依赖型神经退行性疾病
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摘要
人类泛酸激酶依赖型神经退行性疾病(Pantothenate Kinase-Associated Neurodegeneration,PKAN)是一种严重的常染色体隐性遗传性疾病。其典型症状为运动机能障碍、寿命缩短、基底核核团铁积累和神经细胞退行性病变。PKAN的致病基因是人泛酸激酶2(PANK2)基因,目前其发病机制尚不明确:一、PKAN的发病是否因为PanK2泛酸激酶活性的丧失还不确定。另外,PanK2是人PanK家族成员中唯一定位在线粒体的蛋白,对其特性缺乏体内研究支持,还不清楚它与细胞质定位的其他PanK有何不同,也不清楚这种特殊性是否与PKAN的发病相关。由于PanK2敲除的小鼠模型无法很好地模拟PKAN的疾病表征,也无法针对上述问题开展研究;为此,我们需要建立一个新的动物模型。
果蝇中只有一个PANK同源基因fbl, fbl突变果蝇会表现出明显的异常。本研究中,我们以fbl果蝇为基础,在其遗传背景下表达了人PanK2的致病突变,建立了PKAN的果蝇模型。该果蝇模型忠实地模仿了PKAN病人的症状和病理学变化。利用此模型,我们发现果蝇Fbl是人PanK2的直系同源蛋白,它们的亚细胞定位与生理活性十分相似;证明了PKAN的严重程度与体内泛酸激酶总活性直接相关,而并非由其它特殊功能引起;还发现中枢神经系统功能和精子发育对体内泛酸激酶活性变化最敏感,这种敏感缺陷不能被胞质PanK(PanK3和4)挽救;最后,我们演示了如何利用果蝇模型进行PKAN的治疗性药物初筛,寻找有效的化合物。我们的研究结果暗示,PanK2在线粒体外没有活性;相反,其它胞质PanK却是在胞质中有活性而在线粒体中没有。这种区别说明定位在线粒体和胞质PanK的调节机制差异很大。同时,PanK2可能是比其他胞质PanK体内活性更强的泛酸激酶。
简而言之,本研究中我们建立起一个可以用来研究PKAN发病机制的新的动物模型,并进一步探索了PKAN的病发机制和治疗方法。希望此工作能够加深我们对于PKAN的理解,并对后人的研究有所裨益。
Pantothenate Kinase-Associated Neurodegenerative disease (PKAN) is a severe autosomal recessive human neurodegenerative disease. The typical clinical features of PKAN syndrome include motor abnormalities, reduced lifespans, iron accumulation and neurological degeneration in globus pallidus. PKAN is caused by mutations in the human pantothenate kinase 2 (PANK2) gene, but the pathological mechanism of PKAN is still unknown. PanK2 is the only mitochondria protein among four members of human PanK family. It is unclear whether the differences exist between mitochondrial and cytosolic PanKs, nor whether the subcellular localization is related to PKAN pathogenesis. Since the PanK2 knock-out mice could not reproduce symptoms of the disease, a new model is necessary for further understanding of the mechenism of PKAN.
Unlike human and mouse, Drosophila has only one PanK homologue, Fbl. The fbl mutation causes severe abnomalities to fly. In this study, we establish a Drosophila model for human PKAN by introducing mutated forms of human PanK2 into fbl flies. This model faithfully exhibits many behavioral and pathological features reminiscent of PKAN patients. Using this model, we prove that Fbl is the ortholog of human PanK2, with similar subcellular localizations and biological functions, and their localizations are important for their activities. Furthermore, the severity of the disease is strictly correlated with the level of pantothenate kinase activity in vivo. We also find that the spermatogensis and central nerve system function are the most vulnerale biological processes in animals. Finally, a preliminary drug screen is performed in fbl flies searching for helpful compunds for PKAN patients. Our results indicate that PKAN is reliably due to the reduction of pantothenate kinase activity, but not other functions. PanK2 is not active outside mitochondria, while cytosolic PanKs are not active inside mitochondria. And PanK2 might have the highest pantothenate kinase activity in vivo.
Conclusively, in this study, we build up a new animal model for human PKAN disease, and further explore the detailed mechanism and search for potential drugs of Pantothenate Kinase-Associated Neurodegeneration. We hope this work would help us to understand the underline nature of PKAN and could benefit others who also concern this question.
果蝇中只有一个PANK同源基因fbl, fbl突变果蝇会表现出明显的异常。本研究中,我们以fbl果蝇为基础,在其遗传背景下表达了人PanK2的致病突变,建立了PKAN的果蝇模型。该果蝇模型忠实地模仿了PKAN病人的症状和病理学变化。利用此模型,我们发现果蝇Fbl是人PanK2的直系同源蛋白,它们的亚细胞定位与生理活性十分相似;证明了PKAN的严重程度与体内泛酸激酶总活性直接相关,而并非由其它特殊功能引起;还发现中枢神经系统功能和精子发育对体内泛酸激酶活性变化最敏感,这种敏感缺陷不能被胞质PanK(PanK3和4)挽救;最后,我们演示了如何利用果蝇模型进行PKAN的治疗性药物初筛,寻找有效的化合物。我们的研究结果暗示,PanK2在线粒体外没有活性;相反,其它胞质PanK却是在胞质中有活性而在线粒体中没有。这种区别说明定位在线粒体和胞质PanK的调节机制差异很大。同时,PanK2可能是比其他胞质PanK体内活性更强的泛酸激酶。
简而言之,本研究中我们建立起一个可以用来研究PKAN发病机制的新的动物模型,并进一步探索了PKAN的病发机制和治疗方法。希望此工作能够加深我们对于PKAN的理解,并对后人的研究有所裨益。
Pantothenate Kinase-Associated Neurodegenerative disease (PKAN) is a severe autosomal recessive human neurodegenerative disease. The typical clinical features of PKAN syndrome include motor abnormalities, reduced lifespans, iron accumulation and neurological degeneration in globus pallidus. PKAN is caused by mutations in the human pantothenate kinase 2 (PANK2) gene, but the pathological mechanism of PKAN is still unknown. PanK2 is the only mitochondria protein among four members of human PanK family. It is unclear whether the differences exist between mitochondrial and cytosolic PanKs, nor whether the subcellular localization is related to PKAN pathogenesis. Since the PanK2 knock-out mice could not reproduce symptoms of the disease, a new model is necessary for further understanding of the mechenism of PKAN.
Unlike human and mouse, Drosophila has only one PanK homologue, Fbl. The fbl mutation causes severe abnomalities to fly. In this study, we establish a Drosophila model for human PKAN by introducing mutated forms of human PanK2 into fbl flies. This model faithfully exhibits many behavioral and pathological features reminiscent of PKAN patients. Using this model, we prove that Fbl is the ortholog of human PanK2, with similar subcellular localizations and biological functions, and their localizations are important for their activities. Furthermore, the severity of the disease is strictly correlated with the level of pantothenate kinase activity in vivo. We also find that the spermatogensis and central nerve system function are the most vulnerale biological processes in animals. Finally, a preliminary drug screen is performed in fbl flies searching for helpful compunds for PKAN patients. Our results indicate that PKAN is reliably due to the reduction of pantothenate kinase activity, but not other functions. PanK2 is not active outside mitochondria, while cytosolic PanKs are not active inside mitochondria. And PanK2 might have the highest pantothenate kinase activity in vivo.
Conclusively, in this study, we build up a new animal model for human PKAN disease, and further explore the detailed mechanism and search for potential drugs of Pantothenate Kinase-Associated Neurodegeneration. We hope this work would help us to understand the underline nature of PKAN and could benefit others who also concern this question.
引文
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Ching KH, Westaway SK, Gitschier J, et al. 2002. HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology 58(11):1673-1674.
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Ballatore C, Lee VM, Trojanowski JQ. 2007. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci 8(9):663-672.
Barbeito AG, Garringer HJ, Baraibar MA, et al. 2009. Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene. J Neurochem 109(4):1067-1078.
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Bene R, Antic S, Budisic M, et al. 2009. Parkinson's disease. Acta Clin Croat 48(3):377-380.
Bilen J, Bonini NM. 2005. Drosophila as a model for human neurodegenerative disease. Annu Rev Genet 39:153-171.
Bonini NM. 2001. Drosophila as a genetic approach to human neurodegenerative disease. Parkinsonism Relat Disord 7(3):171-175.
Bonini NM, Fortini ME. 2003. Human neurodegenerative disease modeling using Drosophila. Annu Rev Neurosci 26:627-656.
Bosveld F, Rana A, van der Wouden PE, et al. 2008. De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system. Hum Mol Genet 17(13):2058-2069.
Brand AH, Perrimon N. 1993. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118(2):401-415.
Castellani RJ, Nunomura A, Lee HG, et al. 2008. Phosphorylated tau: toxic, protective, or none of the above. J Alzheimers Dis 14(4):377-383.
Chen X, Shen D, Zhou B. 2006. Analysis of the temperature-sensitive mutation of Escherichia coli pantothenate kinase reveals YbjN as a possible protein stabilizer. Biochem Biophys Res Commun 345(2):834-842.
Ching KH, Westaway SK, Gitschier J, et al. 2002. HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology 58(11):1673-1674.
Claros MG, Vincens P. 1996. Computational method to predict mitochondrially imported proteins and their targeting sequences. Eur J Biochem 241(3):779-786.
Curtis AR, Fey C, Morris CM, et al. 2001. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28(4):350-354.
Dahms SO, Hoefgen S, Roeser D, et al. 2010. Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein. Proc Natl Acad Sci U S A.
Ertekin-Taner N. 2007. Genetics of Alzheimer's disease: a centennial review. Neurol Clin 25(3):611-667, v.
Feany MB, Bender WW. 2000. A Drosophila model of Parkinson's disease. Nature 404(6776):394-398.
Flaks JG, Leboy PS, Birge EA, et al. 1966. Mutations and genetics concerned with the ribosome. Cold Spring Harb Symp Quant Biol 31:623-631.
Fuller MT. 1998. Genetic control of cell proliferation and differentiation in Drosophila spermatogenesis. Semin Cell Dev Biol 9(4):433-444.
Gregory A, Hayflick SJ. 2005. Neurodegeneration with brain iron accumulation. Folia Neuropathol 43(4):286-296.
Gregory A, Polster BJ, Hayflick SJ. 2009. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 46(2):73-80.
Hardy J. 2002. Pathways to primary neurodegenerative disease. Neurologia 17(8):399-401.
Hauptmann S, Keil U, Scherping I, et al. 2006. Mitochondrial dysfunction in sporadic and genetic Alzheimer's disease. Exp Gerontol 41(7):668-673.
Hayflick SJ, Westaway SK, Levinson B, et al. 2003. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 348(1):33-40.
Hirtz D, Thurman DJ, Gwinn-Hardy K, et al. 2007. How common are the "common" neurologic disorders? Neurology 68(5):326-337.
Hong BS, Senisterra G, Rabeh WM, et al. 2007. Crystal structures of human pantothenate kinases. Insights into allosteric regulation and mutations linked to a neurodegeneration disorder. J Biol Chem 282(38):27984-27993.
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