Parkin reverses intracellular beta-amyloid accumulation and its negative effects on proteasome function.
Parkin reverses intracellular beta-amyloid accumulation and its negative effects on proteasome function.
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Parkin 可逆转细胞内 β-淀粉样蛋白的积累及其对蛋白酶体功能的负面影响。
DOI：
10.1002/jnr.22178
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发表时间：
2010-01
影响因子：
4.2
通讯作者：
Querfurth, Henry W.
中科院分区：
文献类型：
--
作者：
Rosen, Kenneth M.;Moussa, Charbel E. -H.;Lee, Han-Kyu;Kumar, Pravir;Kitada, Tohru;Qin, Gangjian;Fu, Qinghao;Querfurth, Henry W.
细胞内β-淀粉样蛋白（Aβ42）的积累在阿尔茨海默病（AD）发病机制中的重要性日益受到重视。引起关注的Aβ清除机制包括IDE/脑啡肽酶降解和抗体介导的免疫细胞摄取。然而，泛素-蛋白酶体系统（UPS）在细胞Aβ处理中的作用尚未得到充分研究。E3泛素连接酶Parkin靶向几种蛋白质用于UPS降解，并且Parkin突变是常染色体隐性帕金森病的主要原因。我们测试了帕金是否具有交叉功能，以靶向AD中的错误折叠蛋白，用于SH-SY 5 Y和原代神经元细胞中的蛋白酶体依赖性清除。野生型帕金大大降低了细胞内Aβ42的稳态水平，这一作用被蛋白酶体抑制剂所消除。细胞内Aβ42蓄积降低细胞活力和蛋白酶体活性。因此，帕金逆转了这两种效应。Aβ或Parkin引起的线粒体ATP生成变化不能解释其对蛋白酶体的影响。Parkin敲低导致Aβ蓄积。在AD脑中，发现Parkin与Aβ相互作用，其水平降低。因此，帕金具有细胞保护作用，部分是通过蛋白酶体依赖性途径增加细胞Aβ的清除。
The significance of intracellular β-amyloid (Aβ42) accumulation is increasingly recognized in Alzheimer's disease (AD) pathogenesis. Aβ removal mechanisms that have attracted attention include IDE/neprilysin degradation and antibody-mediated uptake by immune cells. However, the role of the ubiquitin-proteasome system (UPS) in the disposal of cellular Aβ has not been fully explored. The E3 ubiquitin ligase Parkin targets several proteins for UPS degradation, and Parkin mutations are the major cause of autosomal recessive Parkinson's disease. We tested whether Parkin has cross-function to target misfolded proteins in AD for proteasome-dependent clearance in SH-SY5Y and primary neuronal cells. Wild-type Parkin greatly decreased steady-state levels of intracellular Aβ42, an action abrogated by proteasome inhibitors. Intracellular Aβ42 accumulation decreased cell viability and proteasome activity. Accordingly, Parkin reversed both effects. Changes in mitochondrial ATP production from Aβ or Parkin did not account for their effects on the proteasome. Parkin knock-down led to accumulation of Aβ. In AD brain, Parkin was found to interact with Aβ and its levels were reduced. Thus, Parkin is cytoprotective, partially by increasing the removal of cellular Aβ through a proteasome-dependent pathway.
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DOI：
10.1007/s004060050102
发表时间：
1999-12-01
影响因子：
4.7
作者：
Hartmann, T
通讯作者：
Hartmann, T
影响因子：
4.8
作者：
Caspersen, C;Wang, N;Yan, SD
通讯作者：
Yan, SD
影响因子：
2.1
作者：
Chafekar, Sidhartha M.;Zwart, Rob;Scheper, Wiep
通讯作者：
Scheper, Wiep
影响因子：
4.7
作者：
Ding, QX;Keller, JN
通讯作者：
Keller, JN
影响因子：
4.8
作者：
GREGORI, L;FUCHS, C;GOLDGABER, D
通讯作者：
GOLDGABER, D