Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.

摘要: Inclusions composed of α-synuclein (α-syn), i.e., Lewy bodies (LBs) and neurites (LNs), define synucleinopathies including Parkinson's disease (PD) dementia with (DLB). Here, we demonstrate that preformed fibrils generated from full-length truncated recombinant α-syn enter primary neurons, probably by adsorptive-mediated endocytosis, promote recruitment soluble endogenous into insoluble PD-like LBs LNs. Remarkably, was sufficient for formation these aggregates, overexpression wild-type or mutant not required. LN-like pathology first developed in axons propagated to form LB-like inclusions perikarya. Accumulation pathologic led selective decreases synaptic proteins, progressive impairments neuronal excitability connectivity, and, eventually, neuron death. Thus, our data contribute important insights the etiology pathogenesis their impact on functions, they provide a model discovering therapeutics targeting α-syn-mediated neurodegeneration.