Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein.
Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein.
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DOI：
10.1038/emm.2013.45
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发表时间：
2013-05-10
影响因子：
12.8
通讯作者：
Lee, Seung-Jae
中科院分区：
文献类型：
--
作者：
Lee, He-Jin;Cho, Eun-Duk;Lee, Kyung Won;Kim, Jung-Hyun;Cho, Ssang-Goo;Lee, Seung-Jae
异常蛋白质聚集是包括帕金森病(PD)在内的许多神经退行性疾病的主要特征。α-突触核蛋白聚集体和路易小体在细胞质内沉积，常见于帕金森病和其他α-突触核病，被认为与无效的细胞清除机制有关，如蛋白酶体和自噬/溶酶体途径。α-突触核蛋白聚集体聚集在神经元胞浆中，导致神经元发生许多自主性改变。然而，它也可以通过聚集体的跨细胞传递来影响邻近的细胞。事实上，尸检研究已经假设路易氏病变会在大脑区域中逐渐扩散。我们测试了抑制α-突触核蛋白表达细胞中的自噬/溶酶体途径是否会增加α-突触核蛋白的分泌，从而影响邻近细胞中α-突触核蛋白的沉积和活性。我们的结果表明，自噬抑制，通过药物和遗传方法，导致α-突触核蛋白的胞吐增加。在表达α突触核蛋白的供体细胞和受体细胞的混合培养中，自噬抑制导致跨细胞α突触核蛋白传递增加。这种蛋白质传递的增加与受体细胞中凋亡细胞死亡的增加相一致。这些结果表明，自噬活性降低可能导致α-突触核蛋白聚集体的低效率清除，导致α-突触核蛋白胞吐增加，从而促进邻近神经元中α-突触核蛋白的沉积和细胞死亡。这一发现提供了自噬功能障碍和路易氏病理进行性传播之间的潜在联系。
The accumulation of abnormal protein aggregates is a major characteristic of many neurodegenerative disorders, including Parkinson's disease (PD). The intracytoplasmic deposition of α-synuclein aggregates and Lewy bodies, often found in PD and other α-synucleinopathies, is thought to be linked to inefficient cellular clearance mechanisms, such as the proteasome and autophagy/lysosome pathways. The accumulation of α-synuclein aggregates in neuronal cytoplasm causes numerous autonomous changes in neurons. However, it can also affect the neighboring cells through transcellular transmission of the aggregates. Indeed, a progressive spreading of Lewy pathology among brain regions has been hypothesized from autopsy studies. We tested whether inhibition of the autophagy/lysosome pathway in α-synuclein-expressing cells would increase the secretion of α-synuclein, subsequently affecting the α-synuclein deposition in and viability of neighboring cells. Our results demonstrated that autophagic inhibition, via both pharmacological and genetic methods, led to increased exocytosis of α-synuclein. In a mixed culture of α-synuclein-expressing donor cells with recipient cells, autophagic inhibition resulted in elevated transcellular α-synuclein transmission. This increase in protein transmission coincided with elevated apoptotic cell death in the recipient cells. These results suggest that the inefficient clearance of α-synuclein aggregates, which can be caused by reduced autophagic activity, leads to elevated α-synuclein exocytosis, thereby promoting α-synuclein deposition and cell death in neighboring neurons. This finding provides a potential link between autophagic dysfunction and the progressive spread of Lewy pathology.
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