Definition of a Molecular Pathway Mediating α-Synuclein Neurotoxicity
Definition of a Molecular Pathway Mediating α-Synuclein Neurotoxicity
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DOI：
10.1523/jneurosci.4650-14.2015
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发表时间：
2015-04-01
影响因子：
5.3
通讯作者：
Suedhof, Thomas C.
中科院分区：
文献类型：
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作者：
Burre, Jacqueline;Sharma, Manu;Suedhof, Thomas C.
α-突触核蛋白在突触处生理上陪伴SNARE复合物组装，但在病理上错误折叠成神经毒性聚集体，所述聚集体是神经退行性疾病（例如帕金森病）的特征，并且在帕金森病发病过程中可能从一个神经元扩散到整个脑中的下一个神经元。在正常神经末梢中，α-突触核蛋白以天然未折叠的单体的胞质形式与由陪伴SNARE复合物组装的α-螺旋多聚体种类组成的膜结合形式之间的平衡存在。虽然α-突触核蛋白的神经毒性已得到充分证实，但α-突触核蛋白的天然构象与其病理性聚集之间的关系仍不完全清楚;最重要的是，尚不清楚α-突触核蛋白的聚集是否源于其单体胞质或寡聚体膜结合形式。在这里，我们解决这个问题，通过引入α-突触核蛋白的点突变，阻止膜结合，然后通过评估α-突触核蛋白聚集和神经毒性的影响，阻止膜结合。我们表明，膜结合可抑制α-突触核蛋白聚集;相反，阻断膜结合可增强α-突触核蛋白聚集。小鼠黑质中野生型和突变型α-突触核蛋白的立体定向病毒表达表明，阻断α-突触核蛋白膜结合显著增强其体内神经毒性。我们的数据描绘了α-突触核蛋白的折叠途径，其范围从生理多聚体、α-螺旋和膜结合物质（其在单体天然未折叠形式上充当SNARE复合物伴侣）到体内神经毒性的淀粉样蛋白样聚集体。
alpha-Synuclein physiologically chaperones SNARE-complex assembly at the synapse but pathologically misfolds into neurotoxic aggregates that are characteristic for neurodegenerative disorders, such as Parkinson's disease, and that may spread from one neuron to the next throughout the brain during Parkinson's disease pathogenesis. In normal nerve terminals, alpha-synuclein is present in an equilibrium between a cytosolic form that is natively unfolded and monomeric and a membrane-bound form that is composed of an alpha-helical multimeric species that chaperones SNARE-complex assembly. Although the neurotoxicity of alpha-synuclein is well established, the relationship between the native conformations of alpha-synuclein and its pathological aggregation remain incompletely understood; most importantly, it is unclear whether alpha-synuclein aggregation originates from its monomeric cytosolic or oligomeric membrane-bound form. Here, we address this question by introducing into alpha-synuclein point mutations that block membrane binding and by then assessing the effect of blocking membrane binding on alpha-synuclein aggregation and neurotoxicity. We show that membrane binding inhibits alpha-synuclein aggregation; conversely, blocking membrane binding enhances alpha-synuclein aggregation. Stereotactic viral expression of wild-type and mutant alpha-synuclein in the substantia nigra of mice demonstrated that blocking alpha-synuclein membrane binding significantly enhanced its neurotoxicity in vivo. Our data delineate a folding pathway for alpha-synuclein that ranges from a physiological multimeric, alpha-helical, and membrane- bound species that acts as a SNARE-complex chaperone over a monomeric, natively unfolded form to an amyloid-like aggregate that is neurotoxic in vivo.