Gallardo Gilbert, Schlüter Oliver M, Südhof Thomas C
Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9111, USA.
Nat Neurosci. 2008 Mar;11(3):301-8. doi: 10.1038/nn2058. Epub 2008 Feb 24.
Pathogenic aggregates of alpha-synuclein are thought to contribute to the development of Parkinson's disease. Inclusion bodies containing alpha-synuclein are present in Parkinson's disease and other neurodegenerative diseases, including Alzheimer's disease. Moreover, alpha-synuclein mutations are found in cases of familial Parkinson's disease, and transgenic overexpression of alpha-synuclein causes neurodegeneration in mice. The molecular mechanisms involved, however, remain incompletely understood. Here we show that, in transgenic mice, alpha-synuclein induced neurodegeneration involves activation of the ubiquitin/proteasome system, a massive increase in apolipoprotein E (ApoE) levels and accumulation of insoluble mouse Abeta. ApoE was not protective, but was injurious, as deletion of ApoE delayed the neurodegeneration caused by alpha-synuclein and suppressed the accumulation of Abeta. Our data reveal a molecular link between central pathogenic mechanisms implicated in Parkinson's disease and Alzheimer's disease and suggest that intracellular alpha-synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE.
α-突触核蛋白的致病性聚集体被认为与帕金森病的发展有关。含有α-突触核蛋白的包涵体存在于帕金森病和其他神经退行性疾病中，包括阿尔茨海默病。此外，在家族性帕金森病病例中发现了α-突触核蛋白突变，并且α-突触核蛋白的转基因过表达会导致小鼠神经退行性变。然而，其中涉及的分子机制仍未完全了解。在此我们表明，在转基因小鼠中，α-突触核蛋白诱导的神经退行性变涉及泛素/蛋白酶体系统的激活、载脂蛋白E（ApoE）水平的大量增加以及不溶性小鼠β淀粉样蛋白（Aβ）的积累。ApoE并无保护作用，反而具有损害性，因为敲除ApoE可延缓由α-突触核蛋白引起的神经退行性变并抑制Aβ的积累。我们的数据揭示了帕金森病和阿尔茨海默病所涉及的中枢致病机制之间的分子联系，并表明细胞内α-突触核蛋白至少部分通过激活涉及ApoE的细胞外信号通路而具有致病性。
