Coupling endoplasmic reticulum stress to the cell death program in dopaminergic cells: effect of paraquat.
Coupling endoplasmic reticulum stress to the cell death program in dopaminergic cells: effect of paraquat.
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DOI：
10.1007/s12017-008-8047-9
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发表时间：
2008
影响因子：
3.5
通讯作者：
Rao, Rammohan V.
中科院分区：
文献类型：
--
作者：
Chinta, Shankar J.;Rane, Anand;Poksay, Karen S.;Bredesen, Dale E.;Andersen, Julie K.;Rao, Rammohan V.
帕金森病（PD）的特征是氧化应激和错误折叠（未折叠、交替折叠或突变）蛋白的积累，伴随多巴胺能神经元的相关损失。氧化应激和积累的错误折叠蛋白引起细胞反应，包括内质网（ER）应激反应，可以保护细胞免受错误折叠蛋白的毒性积累。然而，慢性ER应激和过量错误折叠蛋白质的积累压倒了细胞的“质量控制”系统，并损害了旨在促进正确折叠和降解错误蛋白质的保护机制，最终导致细胞器功能障碍和神经元细胞死亡。百草枯属于一类联吡啶除草剂，可引发氧化应激和多巴胺能细胞死亡。流行病学研究表明，长期接触百草枯会增加患帕金森病的风险。本研究旨在确定百草枯在触发细胞应激，特别是内质网应激中的作用，并阐明内质网应激与多巴胺能细胞死亡的耦合途径。我们证明，百草枯触发内质网应激，细胞功能障碍，多巴胺能细胞死亡。p23是一种小的辅伴侣蛋白，在百草枯触发的ER应激诱导的细胞死亡期间被切割，并且p23的半胱天冬酶切割位点的阻断与细胞死亡的减少有关。百草枯还抑制蛋白酶体的活性，而蛋白酶体的活性可能进一步触发错误折叠蛋白的积累，导致内质网应激。我们的研究结果表明p23在PD相关的程序性细胞死亡中具有保护作用。这些数据还强调了ER、半胱天冬酶和蛋白酶体系统在ER应激诱导的细胞死亡过程中的参与。
Parkinson’s disease (PD) features oxidative stress and accumulation of misfolded (unfolded, alternatively folded, or mutant) proteins with associated loss of dopaminergic neurons. Oxidative stress and the accumulated misfolded proteins elicit cellular responses that include an endoplasmic reticulum (ER) stress response that may protect cells against the toxic buildup of misfolded proteins. Chronic ER stress and accumulation of misfolded proteins in excessive amounts, however, overwhelm the cellular ‘quality control’ system and impair the protective mechanisms designed to promote correct folding and degrade faulty proteins, ultimately leading to organelle dysfunction and neuronal cell death. Paraquat belongs to a class of bipyridyl herbicides and triggers oxidative stress and dopaminergic cell death. Epidemiological studies suggest an increased risk for developing PD following chronic exposure to paraquat. The present study was carried out to determine the role of paraquat in triggering cellular stress particularly ER stress and to elucidate the pathways that couple ER stress to dopaminergic cell death. We demonstrate that paraquat triggers ER stress, cell dysfunction, and dopaminergic cell death. p23, a small co-chaperone protein, is cleaved during ER stress-induced cell death triggered by paraquat and blockage of the caspase cleavage site of p23 was associated with decreased cell death. Paraquat also inhibits proteasomal activity that may further trigger accumulation of misfolded proteins resulting in ER stress. Our results indicate a protective role for p23 in PD-related programmed cell death. The data also underscore the involvement of ER, caspases, and the proteasomal system in ER stress-induced cell death process.
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影响因子：
82.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
56.9
作者：
Bose, S;Weikl, T;Buchner, J
通讯作者：
Buchner, J
DOI：
10.1016/j.biocel.2004.09.009
发表时间：
2005-05-01
影响因子：
4
作者：
Chinta, SJ;Andersen, JK
通讯作者：
Andersen, JK
影响因子：
5.3
作者：
Andersen, JK
通讯作者：
Andersen, JK
影响因子：
15.9
作者：
Forman, MS;Lee, VMY;Trojanowski, JQ
通讯作者：
Trojanowski, JQ