Alterations in lysosomal and proteasomal markers in Parkinson's disease: Relationship to alpha-synuclein inclusions
Alterations in lysosomal and proteasomal markers in Parkinson's disease: Relationship to alpha-synuclein inclusions
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DOI：
10.1016/j.nbd.2009.05.023
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发表时间：
2009-09-01
影响因子：
6.1
通讯作者：
Kordower, Jeffrey H.
中科院分区：
文献类型：
--
作者：
Chu, Yaping;Dodiya, Hemraj;Kordower, Jeffrey H.
我们探讨了泛素蛋白酶体系统(UPS)与溶酶体标志物的关系以及帕金森病(PD)黑质神经元中α-突触核蛋白(α-SYN)包涵体的形成。与年龄匹配的对照组相比，PD黑质神经元中溶酶体相关膜蛋白1(LAMP1)、组织蛋白酶D(CatD)和热休克蛋白73(HSP73)的免疫反应性显著降低。这种减少在含有α-突触核包涵体的黑质神经元中明显更大。在PD黑质神经元中，20S蛋白酶体的免疫反应性也同样降低，但仅在含有包涵体的细胞中减少。老年对照组大鼠黑质神经元中有α-syn蛋白表达，但呈非聚集状态，α-syn阳性与阴性黑质神经元的LAMP1、CatD、HSP73或20S蛋白酶体免疫反应无明显差异。用病毒载体靶向突变的人α-syn在大鼠黑质中的过度表达显示，在显示α-syn-ir包涵体的神经元中，溶酶体和蛋白酶体标记显著减少。这些发现表明α-SYN聚集是与蛋白酶体和溶酶体下降相关的一个关键特征，并支持PD细胞变性与蛋白酶体和溶酶体功能障碍、蛋白质清除受损以及蛋白质聚集和聚集导致细胞死亡有关的假说。(C)2009年，爱思唯尔公司出版。
We explored the relationship between ubiquitin proteasome system (UPS) and lysosomal markers and the formation of alpha-synuclein (alpha-syn) inclusions in nigral neurons in Parkinson disease (PD). Lysosome Associated Membrane Protein 1(LAMP1), Cathepsin D (CatD), and Heat Shock Protein73 (HSP73) immunoreactivity were significantly decreased within PD nigral neurons when compared to age-matched controls. This decrease was significantly greater in nigral neurons that contained alpha-syn inclusions. Immunoreactivity for 20S proteasome was similarly reduced in PD nigral neurons, but only in cells that contained inclusions. In aged control brains, there is staining for alpha-syn protein, but it is non-aggregated and there is no difference in LAMP1, CatD, HSP73 or 20S proteasome immunoreactivity between alpha-syn positive or negative neuromelanin-laden nigral neurons. Targeting over-expression of mutant human alpha-syn in the rat substantia nigra using viral vectors revealed that lysosomal and proteasomal markers were significantly decreased in the neurons that displayed alpha-syn-ir inclusions. These findings suggest that alpha-syn aggregation is a key feature associated with decline of proteasome and lysosome and support the hypothesis that cell degeneration in PD involves proteosomal and lysosomal dysfunction, impaired protein clearance, and protein accumulation and aggregation leading to cell death. (C) 2009 Published by Elsevier Inc.