VPS41, a protein involved in lysosomal trafficking, is protective in Caenorhabditis elegans and mammalian cellular models of Parkinson's disease.
VPS41, a protein involved in lysosomal trafficking, is protective in Caenorhabditis elegans and mammalian cellular models of Parkinson's disease.
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DOI：
10.1016/j.nbd.2009.10.011
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发表时间：
2010-02
影响因子：
6.1
通讯作者：
Standaert DG
中科院分区：
文献类型：
--
作者：
Ruan Q;Harrington AJ;Caldwell KA;Caldwell GA;Standaert DG
VPS 41是一种通过高通量RNAi筛选C.优美的VPS 41与PD的发病机制存在合理的机制联系，因为在酵母中，已知VPS 41参与蛋白质向溶酶体系统的运输，最近的几条证据表明溶酶体系统功能障碍在α-突触核蛋白（α-syn）的神经毒性中具有重要意义。我们发现人型VPS 41（hVPS 41）的表达可防止α-syn过表达和6-羟基多巴胺（6-OHDA）神经毒性诱导的C.优雅的。在用hVPS 41稳定转染的SH-SY 5 Y神经母细胞瘤细胞系中，我们确定该蛋白质的存在赋予针对神经毒素6-OHDA和鱼藤酮的保护。过表达hVPS 41并不改变这些神经毒素诱导的线粒体膜去极化。然而，hVPS 41确实阻断了凋亡级联中的下游事件，包括半胱天冬酶-9和半胱天冬酶-3的活化以及PARP裂解。我们还观察到，在用鱼藤酮处理后，hVPS 41减少了SH-SY 5 Y细胞中不溶性高分子量形式的α-syn的积累。这些数据表明，hVPS 41在PD的无脊椎动物和细胞模型中对α-syn和神经毒性介导的损伤具有保护作用。这些保护功能可能与增强错误折叠或聚集蛋白（包括α-syn）的清除有关。我们的研究表明，hVPS 41可能是一个有用的目标，为开发人类PD的治疗策略。
VPS41 is a protein identified as a potential therapeutic target for Parkinson's disease (PD) as a result of a high-throughput RNAi screen in C. elegans. VPS41 has a plausible mechanistic link to the pathogenesis of PD, as in yeast it is known to participate in trafficking of proteins to the lysosomal system and several recent lines of evidence have pointed to the importance of lysosomal system dysfunction in the neurotoxicity of alpha-synuclein (α-syn). We found that expression of the human form of VPS41 (hVPS41) prevents dopamine (DA) neuron loss induced by α-syn overexpression and 6-hydroxydopamine (6-OHDA) neurotoxicity in C. elegans. In SH-SY5Y neuroblastoma cell lines stably transfected with hVPS41, we determined that presence of this protein conferred protection against the neurotoxins 6-OHDA and rotenone. Overexpression of hVPS41 did not alter the mitochondrial membrane depolarization induced by these neurotoxins. hVPS41 did, however, block downstream events in the apoptotic cascade including activation of caspase-9 and caspase-3, and PARP cleavage. We also observed that hVPS41 reduced the accumulation of insoluble high molecular weight forms of α-syn in SH-SY5Y cells after treatment with rotenone. These data show that hVPS41 is protective against both α-syn and neurotoxic-mediated injury in invertebrate and cellular models of PD. These protective functions may be related to enhanced clearance of misfolded or aggregated protein, including α-syn. Our studies indicate that hVPS41 may be a useful target for developing therapeutic strategies for human PD.
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影响因子：
3.6
作者：
Cullen, Valerie;Lindfors, Maria;Ng, Juliana;Paetau, Anders;Swinton, Erika;Kolodziej, Piotr;Boston, Heather;Saftig, Paul;Woulfe, John;Feany, Mel B.;Myllykangas, Liisa;Schlossmacher, Michael G.;Tyynela, Jaana
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Tyynela, Jaana
影响因子：
3.9
作者：
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通讯作者：
Johnson, EM
影响因子：
4.7
作者：
Hartmann, A;Michel, PP;Hirsch, EC
通讯作者：
Hirsch, EC
影响因子：
2.5
作者：
Fung, HC;Chen, CM;Wu, YR
通讯作者：
Wu, YR
DOI：
10.1097/00005072-199804000-00005
发表时间：
1998-04-01
影响因子：
3.2
作者：
Irizarry, MC;Growdon, W;Hyman, BT
通讯作者：
Hyman, BT