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Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.
Neuron. 2011 Oct 06; 72(1):57-71.N

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.

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Authors+Show Affiliations

Volpicelli-Daley LA
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.
Luk KC
No affiliation info available
Patel TP
No affiliation info available
Tanik SA
No affiliation info available
Riddle DM
No affiliation info available
Stieber A
No affiliation info available
Meaney DF
No affiliation info available
Trojanowski JQ
No affiliation info available
Lee VM
No affiliation info available

MeSH

AnimalsAxonal TransportCell DeathEndocytosisHippocampusHumansLewy BodiesMiceMice, Inbred C57BLNerve DegenerationNerve Tissue ProteinsNeuritesNeuronsPrimary Cell CultureSynapsesVoltage-Sensitive Dye Imagingalpha-Synuclein

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

21982369

Citation

Volpicelli-Daley, Laura A., et al. "Exogenous Α-synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death." Neuron, vol. 72, no. 1, 2011, pp. 57-71.
Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011;72(1):57-71.
Volpicelli-Daley, L. A., Luk, K. C., Patel, T. P., Tanik, S. A., Riddle, D. M., Stieber, A., Meaney, D. F., Trojanowski, J. Q., & Lee, V. M. (2011). Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron, 72(1), 57-71. https://doi.org/10.1016/j.neuron.2011.08.033
Volpicelli-Daley LA, et al. Exogenous Α-synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death. Neuron. 2011 Oct 6;72(1):57-71. PubMed PMID: 21982369.
* Article titles in AMA citation format should be in sentence-case
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, PY - 2011/08/23/accepted PY - 2011/10/11/entrez PY - 2011/10/11/pubmed PY - 2011/12/13/medline SP - 57 EP - 71 JF - Neuron JO - Neuron VL - 72 IS - 1 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. SN - 1097-4199 UR - https://www.unboundmedicine.com/medline/citation/21982369/Exogenous_α_synuclein_fibrils_induce_Lewy_body_pathology_leading_to_synaptic_dysfunction_and_neuron_death_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0896-6273(11)00844-0 DB - PRIME DP - Unbound Medicine ER -