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首页> 外文期刊>Neuron >Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.
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Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.

机译：外源性α-突触核蛋白原纤维诱导路易体病理，导致突触功能障碍和神经元死亡。

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摘要

Inclusions composed of alpha-synuclein (alpha-syn), i.e., Lewy bodies (LBs) and Lewy neurites (LNs), define synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Here, we demonstrate that preformed fibrils generated from full-length and truncated recombinant alpha-syn enter primary neurons, probably by adsorptive-mediated endocytosis, and promote recruitment of soluble endogenous alpha-syn into insoluble PD-like LBs and LNs. Remarkably, endogenous alpha-syn was sufficient for formation of these aggregates, and overexpression of wild-type or mutant alpha-syn was not required. LN-like pathology first developed in axons and propagated to form LB-like inclusions in perikarya. Accumulation of pathologic alpha-syn led to selective decreases in synaptic proteins, progressive impairments in neuronal excitability and connectivity, and, eventually, neuron death. Thus, our data contribute important insights into the etiology and pathogenesis of PD-like alpha-syn inclusions and their impact on neuronal functions, and they provide a model for discovering therapeutics targeting pathologic alpha-syn-mediated neurodegeneration.
机译：由α-突触核蛋白（α-syn）即路易体（LB）和路易神经突（LN）组成的内含物定义了突触核细胞病，包括帕金森氏病（PD）和路易体痴呆（DLB）。在这里，我们证明了从全长和截短的重组α-syn生成的预成纤维可能会通过吸附介导的内吞作用进入初级神经元，并促进将可溶性内源性α-syn募集到不可溶的PD样LB和LN中。明显地，内源性α-syn足以形成这些聚集体，并且不需要野生型或突变体α-syn的过表达。 LN样病理学首先在轴突中发展，并传播到周围核中，形成LB样内含物。病理性α-syn的积累导致突触蛋白的选择性减少，神经元兴奋性和连接性的进行性损伤，最终导致神经元死亡。因此，我们的数据为PD样α-syn夹杂物的病因和发病机理及其对神经元功能的影响提供了重要的见解，它们为发现靶向病理性α-syn介导的神经变性的治疗方法提供了模型。

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