Origins and effects of extracellular α-synuclein:: Implications in Parkinson's disease
Origins and effects of extracellular α-synuclein:: Implications in Parkinson's disease
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DOI：
10.1007/s12031-007-0012-9
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发表时间：
2008-01-01
影响因子：
3.1
通讯作者：
Lee, Seung-Jae
中科院分区：
文献类型：
--
作者：
Lee, Seung-Jae
神经元蛋白α-突触核蛋白的错误折叠和异常聚集已经涉及帕金森病和相关神经障碍（例如路易体痴呆）的发病机制。α-突触核蛋白是一种常规的胞质蛋白，并且被认为以细胞自主的方式仅在神经元细胞质中发挥其致病功能。然而，目前的模型正在受到一系列新的观察结果的挑战，这些观察结果证明了体内和体外细胞外液中存在α-突触核蛋白及其聚集形式。细胞外α-突触核蛋白似乎是通过囊泡内α-突触核蛋白的非常规胞吐作用递送的，尽管确切的机制尚未被表征。与胞质α-突触核蛋白相比，囊泡内α-突触核蛋白易于聚集并且是细胞外聚集体的潜在来源。许多组织培养研究表明，暴露于细胞外α-突触核蛋白聚集体诱导小胶质细胞活化，从星形胶质细胞释放促炎细胞因子和神经毒性。因此，α-突触核蛋白的胞吐作用可能是将退行性变化从一小群细胞放大和扩散到其周围组织的重要机制，并且它可能提供用于阻止疾病进展的治疗靶点。
Misfolding and abnormal aggregation of the neuronal protein alpha-synuclein has been implicated in the pathogenesis of Parkinson's disease and related neurological disorders, such as dementia with Lewy bodies. alpha-synuclein is a conventional cytosolic protein and is thought to exert its pathogenic function exclusively in the neuronal cytoplasm in a cell-autonomous manner. However, the current model is being challenged by a series of new observations that demonstrate the presence of alpha-synuclein and its aggregated forms in the extracellular fluid both in vivo and in vitro. Extracellular alpha-synuclein appears to be delivered by unconventional exocytosis of intravesicular alpha-synuclein, although the exact mechanism has not been characterized. Compared to the cytosolic alpha-synuclein, intravesicular alpha-synuclein is prone to aggregation and the potential source of extracellular aggregates. A number of tissue culture studies suggest that exposure to extracellular alpha-synuclein aggregates induces microglial activation, release of pro-inflammatory cytokines from astrocytes, and neurotoxicity. Thus, exocytosis of alpha-synuclein may be an important mechanism for amplifying and spreading degenerative changes from a small group of cells to its surrounding tissues, and it potentially provides therapeutic targets for halting the progression of the disease.