TY - JOUR
T1 - Exogenous α-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death
AU - Volpicelli-Daley, Laura A.
AU - Luk, Kelvin C.
AU - Patel, Tapan P.
AU - Tanik, Selcuk A.
AU - Riddle, Dawn M.
AU - Stieber, Anna
AU - Meaney, David F.
AU - Trojanowski, John Q.
AU - Lee, Virginia M.Y.
N1 - Funding Information:
Kurt Brunden, James Soper, Linda Kwong, Eddie Lee, and Jing Guo are thanked for reading the manuscript and for helpful discussions, and Patrick O'Brien, Christine Schultheiss, Victoria Kehm, Christina Haas, and Jeffrey Yeh for technical assistance. This work was supported by National Institutes of Health Grants NS053488, the Picower Foundation, the Benaroya Foundation, the RJG Foundation, the Jeff and Anne Keefer fund for Parkinson's Research, the Parkinson Council, the Stein-Bellet Family Fund, and National Institutes of Health Grant NS015202 and Army Research Office W911F-10-1-0526.
PY - 2011/10/6
Y1 - 2011/10/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2011.08.033
DO - 10.1016/j.neuron.2011.08.033
M3 - Article
C2 - 21982369
AN - SCOPUS:80053613574
SN - 0896-6273
VL - 72
SP - 57
EP - 71
JO - Neuron
JF - Neuron
IS - 1
ER -