Exogenous α-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death
By L. Volpicelli-Daley, Kelvin C. Luk, Tapan P. Patel, Selcuk A. Tanik, Dawn M. Riddle, Anna Stieber, D. Meaney, John Q. Trojanowski, V. Lee. Neuron, 2011
1,498 citations recorded by the source corpus.
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.
Subfields: Neurology
View Paper: https://www.semanticscholar.org/paper/c5674f4824217b0f661ed26a651c0ba9bc150518
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In Neurology
- V. Lee
- John Q. Trojanowski
- Christian Haass
- Kelvin C. Luk
- A. Lutz
- K. Winklhofer
- Nicole Exner
- Bin Zhang
Citations in the corpus
- Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. (2019, background): “Growing evidence supports that fibril forms of a-syn, the principal component of LBs, can be transmitted from cell to cell in a prion-like manner (Lee et al., 2010; Luk et al., 2012; Pan-Montojo et al., 2012; Volpicelli-Daley et al., 2011).”
- Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice (2012, background): “…toward neocortical regions with disease pro gression (Braak et al., 2003; Del Tredici and Braak, 2008), the data presented here and recent studies (VolpicelliDaley et al., 2011) indicate that the transmission of pathological Syn can occur bidirectionally within a network of inter connected…”