α-突触核蛋白与CSPα协同作用以预防神经退行性变。

Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration.

作者信息

Chandra Sreeganga, Gallardo Gilbert, Fernández-Chacón Rafael, Schlüter Oliver M, Südhof Thomas C

机构信息

Center for Basic Neuroscience, Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

出版信息

Cell. 2005 Nov 4;123(3):383-96. doi: 10.1016/j.cell.2005.09.028.

DOI:10.1016/j.cell.2005.09.028

PMID:16269331

Abstract

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.

摘要

α-突触核蛋白和半胱氨酸串珠蛋白-α（CSPα）是与神经退行性变独立相关的丰富的突触小泡蛋白。α-突触核蛋白的显性遗传突变会导致帕金森病，但α-突触核蛋白的生理作用仍然未知。CSPα的缺失会在小鼠中产生快速进展的神经退行性变，推测是因为CSPα的共伴侣功能对神经元存活至关重要。在此，我们报告了一个惊人的发现，即α-突触核蛋白的转基因表达消除了由CSPα缺失引起的致死性和神经退行性变。相反，内源性突触核蛋白的缺失会加剧这些表型。CSPα的缺失会抑制SNARE复合体的组装；转基因α-突触核蛋白可改善这种抑制作用。在预防CSPα缺陷小鼠的神经退行性变过程中，α-突触核蛋白并非简单地替代CSPα，而是通过一种需要α-突触核蛋白结合磷脂的下游机制发挥作用。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强大的体内活性，并表明这种活性与CSPα和突触前膜界面上的SNARE蛋白协同发挥作用。