Effects of Excess Brain-Derived Human α-Synuclein on Synaptic Vesicle Trafficking.
Effects of Excess Brain-Derived Human α-Synuclein on Synaptic Vesicle Trafficking.
复制标题
过量脑源性人α-突触核蛋白对突触囊泡运输的影响。
DOI：
10.3389/fnins.2021.639414
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发表时间：
2021
影响因子：
4.3
通讯作者：
Morgan JR
中科院分区：
文献类型：
--
作者：
Román-Vendrell C;Medeiros AT;Sanderson JB;Jiang H;Bartels T;Morgan JR
α-突触核蛋白是一种突触前蛋白，在生理条件下调节突触小泡的运输。然而，在一些神经退行性疾病中，包括帕金森病、路易体痴呆和多系统萎缩，α-突触核蛋白在整个神经元中积聚，包括在突触处，导致突触功能改变、神经毒性以及运动、认知和自主功能障碍。神经元通常既含有单体形式的α-突触核蛋白，也含有多聚体形式的突触核蛋白，人们普遍认为破坏它们之间的平衡会促进聚集和神经毒性。然而，目前尚不清楚α-突触核蛋白的不同分子种类如何影响正常表达α-突触核蛋白的突触。利用Lamprey网状脊髓突触模型，我们先前发现，过量的重组单体或二聚体α-突触核蛋白的急性引入会损害网状蛋白介导的突触小泡内吞作用的不同阶段，导致突触小泡的丢失。在这里，我们通过研究从神经病理正常受试者的脑中分离出来的天然的、生理性的α-突触核蛋白的作用来扩展这一知识，它主要由螺旋折叠的多聚体α-突触核蛋白和少量单体α-突触核蛋白组成。在急性注射过量的人脑来源α-突触核蛋白后，突触小泡丛适度减少，大的、非典型的小泡数量增加，称为“池”。此外，脑源性α-突触核蛋白增加了突触囊泡和脑池的大小，并在活动区诱导了非典型的融合/分裂事件。与单体或二聚体α-突触核蛋白相比，脑源性多聚体α-突触核蛋白似乎不会改变笼蛋白介导的突触囊泡内吞作用。综上所述，这些数据表明，过量的脑源性人类α-突触核蛋白损害了细胞内小泡的运输，并进一步证实了不同分子种类的α-突触核蛋白在突触上产生不同的运输缺陷的观点。这些发现对α-突触核蛋白过量导致突触缺陷和疾病表型的机制提供了深入的见解。
α-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive, and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of α-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here, we expand this knowledge by investigating the effects of native, physiological α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called “cisternae.” In addition, brain-derived α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of α-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.