TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
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DOI：
10.1073/pnas.1305623110
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发表时间：
2013-05-07
影响因子：
11.1
通讯作者：
Bjorklund, Anders
中科院分区：
文献类型：
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作者：
Decressac, Mickael;Mattsson, Bengt;Bjorklund, Anders
α-突触核蛋白的聚集在帕金森病（PD）的发病机制中起主要作用。最近的证据表明，自噬介导的α-突触核蛋白清除的缺陷有助于黑质多巴胺神经元的进行性丧失。使用α-突触核蛋白毒性的体内模型，我们表明，在黑质多巴胺神经元中由过量的细胞水平的α-突触核蛋白诱导的PD样神经退行性变化与溶酶体功能标志物的进行性下降密切相关，伴随着转录因子EB（TFEB）的细胞质保留，自噬-溶酶体途径的主要转录调节因子。在大鼠模型以及人PD中脑中观察到的溶酶体功能的变化通过TFEB的过表达而逆转，TFEB的过表达通过α-突触核蛋白寡聚体的清除提供了强大的神经保护，并且通过A9和A10多巴胺神经元中的microRNA-128介导的TFEB抑制而加重。通过抑制雷帕霉素的哺乳动物靶标延迟TFEB功能的激活阻断了α-突触核蛋白诱导的神经变性和进一步的疾病进展。结果提供了α-突触核蛋白毒性和TFEB功能受损之间的机制联系，并强调TFEB作为诱导α-突触核蛋白诱导的毒性和PD发病机制的关键参与者，从而将TFEB鉴定为旨在PD中神经保护和疾病修饰的治疗的有希望的靶点。
The aggregation of alpha-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of alpha-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of alpha-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of alpha-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of alpha-synuclein oligomers, and were aggravated by microRNA-128-mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked alpha-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between alpha-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of alpha-synuclein-induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.