Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration.
Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration.
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发表时间：
2005
期刊：
影响因子：
64.5
通讯作者：
S. Chandra;G. Gallardo;R. Fernández-Chacón;O. Schlüter;T. Südhof
中科院分区：
文献类型：
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作者：
S. Chandra;G. Gallardo;R. Fernández-Chacón;O. Schlüter;T. Südhof
α-突触核蛋白和半胱氨酸串蛋白-α（CSPalpha）是独立地与神经变性相关的丰富的突触囊泡蛋白。α-突触核蛋白的显性遗传突变导致帕金森病，但α-突触核蛋白的生理作用仍然未知。CSPalpha的缺失在小鼠中产生快速进行性神经变性，可能是因为CSPalpha的辅伴侣功能对于神经元存活是必需的。在这里，我们报告了令人惊讶的发现，α-突触核蛋白的转基因表达消除了CSPalpha缺失引起的致死性和神经变性。相反，内源性突触核蛋白的消融加剧了这些表型。CSPalpha的缺失抑制SNARE复合物组装;转基因α-突触核蛋白改善这种抑制。在预防CSPal α缺陷小鼠的神经变性中，α-突触核蛋白并不简单地取代CSPal α，而是通过需要通过α-突触核蛋白结合磷脂的下游机制起作用。这些观察结果揭示了α-突触核蛋白在保护神经末梢免受损伤方面的强大体内活性，并表明这种活性与突触前膜界面上的CSPalpha和SNARE蛋白一起起作用。
Alpha-synuclein and cysteine-string protein-alpha (CSPalpha) are abundant synaptic vesicle proteins independently linked to neurodegeneration. Dominantly inherited mutations in alpha-synuclein cause Parkinson's disease, but the physiological role of alpha-synuclein remains unknown. Deletion of CSPalpha produces rapidly progressive neurodegeneration in mice, presumably because the cochaperone function of CSPalpha is essential for neuronal survival. Here, we report the surprising finding that transgenic expression of alpha-synuclein abolishes the lethality and neurodegeneration caused by deletion of CSPalpha. Conversely, ablation of endogenous synucleins exacerbates these phenotypes. Deletion of CSPalpha inhibits SNARE complex assembly; transgenic alpha-synuclein ameliorates this inhibition. In preventing neurodegeneration in CSPalpha-deficient mice, alpha-synuclein does not simply substitute for CSPalpha but acts by a downstream mechanism that requires phospholipid binding by alpha-synuclein. These observations reveal a powerful in vivo activity of alpha-synuclein in protecting nerve terminals against injury and suggest that this activity operates in conjunction with CSPalpha and SNARE proteins on the presynaptic membrane interface.