| First Author | Volpicelli-Daley LA | Year | 2011 |
| Journal | Neuron | Volume | 72 |
| Issue | 1 | Pages | 57-71 |
| PubMed ID | 21982369 | Mgi Jnum | J:178534 |
| Mgi Id | MGI:5299252 | Doi | 10.1016/j.neuron.2011.08.033 |
| Citation | Volpicelli-Daley LA, et al. (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72(1):57-71 |
| abstractText | 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. |
