Chaperone-Mediated Autophagy Markers in Parkinson Disease Brains
Chaperone-Mediated Autophagy Markers in Parkinson Disease Brains
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DOI：
10.1001/archneurol.2010.198
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发表时间：
2010-12-01
影响因子：
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通讯作者：
Schapira, Anthony H. V.
中科院分区：
文献类型：
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作者：
Alvarez-Erviti, Lydia;Rodriguez-Oroz, Maria C.;Schapira, Anthony H. V.
目的：探讨伴侣介导的自噬在帕金森病(PD)发病机制中的作用。设计：死后观察研究。地点：伦敦大学学院神经病学研究所临床神经科学系。对象：7例PD、6例阿尔茨海默病(AD)和8例对照脑的尸检标本。主要观察指标：比较PD、AD和对照脑标本黑质致密部和杏仁核中溶酶体相关膜蛋白2A(LAMP2A)和热休克同源蛋白70(Hsc70)的蛋白水平。为了深入了解α-突触核蛋白的周转，研究了该蛋白在多巴胺能细胞系中的降解途径。结果：与年龄匹配的AD和对照组相比，帕金森病患者脑内黑质致密部和杏仁核中伴侣蛋白介导的自噬蛋白LAMP2A和hsc70的表达水平显著降低。这些区域的路易小体含有自噬相关蛋白。我们发现，多巴胺能细胞系中LAMP2A水平的降低降低了伴侣介导的自噬活性，并延长了α-突触核蛋白的半衰期。结论：这些发现表明帕金森病脑内存在伴侣介导的自噬活性降低，为自噬在帕金森病发病机制和路易体形成中的作用提供了证据，并提示这一途径可能是帕金森病的一个合适的治疗靶点。
Objective: To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD).Design: Postmortem observational study.Setting: University Department of Clinical Neuroscience, Institute of Neurology, University College London.Subjects: Postmortem samples from 7 PD, 6 Alzheimer disease (AD), and 8 control brains.Main Outcome Measure: Lysosomal-associated membrane protein 2A (LAMP2A) and heat shock cognate 70 (hsc70) protein levels were compared in the substantia nigra pars compacta and amygdala of PD, AD, and control brain samples. To provide insight into the turnover of alpha-synuclein, degradation pathways for this protein were studied in a dopaminergic cell line.Results: The expression levels of the chaperone-mediated autophagy proteins LAMP2A and hsc70 were significantly reduced in the substantia nigra pars compacta and amygdala of PD brains compared with age-matched AD and control brain samples. Lewy bodies in these regions contained autophagy-related proteins. We demonstrated that decreased LAMP2A levels in dopaminergic cell lines reduced chaperone-mediated autophagy activity and increased the half-life of alpha-synuclein.Conclusions: These findings suggest that there is reduced chaperone-mediated autophagy activity in the PD brain, provide evidence for the role of autophagy in PD pathogenesis and Lewy body formation, and suggest that this pathway may be a suitable therapeutic target in PD.