title: Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.
abstract: Inclusions composed 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 preformed fibrils generated from full-length and truncated recombinant α-syn enter primary neurons, probably 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 and their impact on neuronal functions, and they provide a model for discovering therapeutics targeting pathologic α-syn-mediated neurodegeneration.
authors: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 USA.
authors: Laura A
authors: LA
authors: Volpicelli-Daley
authors: Kelvin C
authors: KC
authors: Luk
authors: Tapan P
authors: TP
authors: Patel
authors: Selcuk A
authors: SA
authors: Tanik
authors: Dawn M
authors: DM
authors: Riddle
authors: Anna
authors: A
authors: Stieber
authors: David F
authors: DF
authors: Meaney
authors: John Q
authors: JQ
authors: Trojanowski
authors: Virginia M-Y
authors: VM
authors: Lee
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D016923:Cell Death / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology / Q000648:ultrastructure; D061251:Primary Cell Culture; D013569:Synapses / Q000378:metabolism / Q000473:pathology*; D056969:Voltage-Sensitive Dye Imaging / Q000379:methods; D051844:alpha-Synuclein / Q000009:adverse effects* / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D051844:alpha-Synuclein