Rab11a and HSP90 regulate recycling of extracellular alpha-synuclein.
Rab11a and HSP90 regulate recycling of extracellular alpha-synuclein.
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DOI：
10.1523/jneurosci.6202-08.2009
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发表时间：
2009-02-04
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
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作者：
Liu J;Zhang JP;Shi M;Quinn T;Bradner J;Beyer R;Chen S;Zhang J
越来越多的证据表明，细胞外α-突触核蛋白（eSNCA）可能通过直接或激活胶质细胞产生神经毒性，在帕金森病（PD）及相关突触核蛋白病的发病机制中发挥重要作用。然而，参与eSNCA在神经元和/或神经胶质中运输的机制仍不清楚。在这里，我们证明了eSNCA可以通过一个由再循环内体调节因子rab 11 a调节的过程重新分泌出神经元，除了被内体-溶酶体系统降解之外。定量蛋白质组学分析也揭示了rab 11 a可能通过其执行其功能的许多蛋白质。热休克蛋白90（HSP 90）是一种与rab 11 a相互作用的候选蛋白。此外，热休克蛋白90抑制剂格尔德霉素，不仅阻止了再分泌的eSNCA，但也减弱了由eSNCA诱导的神经毒性。
Growing evidence suggests that extracellular α-synuclein (eSNCA) may play an important role in the pathogenesis of Parkinson's disease (PD) and related synucleinopathies by producing neurotoxicity directly or via activation of glia. However, the mechanisms involved in the trafficking of eSNCA in neurons and/or glia remain unclear. Here, we demonstrated that eSNCA could be re-secreted out of neurons via a process modulated by a recycling endosome regulator rab11a in addition to being degraded by an endosome-lysosome system. A quantitative proteomic analysis also revealed numerous proteins through which rab11a might execute its function. One of the candidate proteins, heat shock protein 90 (HSP90), was validated to be interacting with rab11a. Furthermore, geldanamycin, an HSP90 inhibitor, not only prevented re-secretion of eSNCA but also attenuated neurotoxicity induced by eSNCA.