α-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models
α-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models
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DOI：
10.1126/science.1129462
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发表时间：
2006-07-21
期刊：
影响因子：
56.9
通讯作者：
Lindquist, Susan
中科院分区：
文献类型：
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作者：
Cooper, Antony A.;Gitler, Aaron D.;Lindquist, Susan
α-突触核蛋白（α-Syn）错误折叠与几种破坏性神经退行性疾病有关，包括帕金森病（PD）。在酵母细胞和神经元中，α-Syn积累具有细胞毒性，但对其正常功能或病理学知之甚少。酵母中α-Syn表达后的最早缺陷是内质网（ER）到高尔基体囊泡运输的阻断。在全基因组筛选中，最大的一类毒性修饰剂是在同一步骤起作用的蛋白质，包括Rab鸟苷三磷酸酶Ypt 1 p，它与细胞质α-Syn包涵体相关。Rab 1（哺乳动物YPT 1同源物）表达升高可保护PD动物模型免受α-Syn诱导的多巴胺能神经元损失。因此，突触核蛋白病可能是由基本细胞功能的破坏引起的，这些功能与特定神经元的独特生物学相互作用，使它们特别脆弱。
Alpha-synuclein (alpha Syn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons alpha Syn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following alpha Syn expression in yeast was a block in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic alpha Syn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against alpha Syn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.