Summary Inclusions comprised of α-synuclein (α-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 pre-formed fibrils generated from full length and truncated recombinant α-syn enter primary neurons, likely by adsorptive-mediated endocytosis and promote recruitment of soluble endogenous α-syn into insoluble PD-like LBs and LNs. Remarkably, endogenous α-syn was sufficient for formation of these aggregates, and overexpression of wild type or mutant α-syn was not required. LN-like pathology first developed in axons and propagated to form LB-like inclusions in perikarya. Accumulation of pathologic α-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 α-syn inclusions, their impact on neuronal functions, and provide a model for discovering therapeutics targeting pathologic α-syn- mediated neurodegeneration.

Background: ␣-Synuclein aggregates and macroautophagy are associated with neurodegeneration. Results: Modulation of macroautophagic activity does not affect ␣-synuclein aggregate levels, although these aggregates cause accumulation of immature autophagosomes. Conclusion: ␣-Synuclein aggregates are resistant to degradation and impair autophagy by delaying autophagosome maturation. Significance: Understanding the impact of ␣-synuclein aggregates on autophagy may help elucidate therapies for ␣-synucleinmediated neurodegeneration.