Formation of Toxic Oligomeric α-Synuclein Species in Living Cells

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Formation of Toxic Oligomeric α-Synuclein Species in Living Cells

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Title: Formation of Toxic Oligomeric α-Synuclein Species in Living Cells
Author: Outeiro, Tiago Fleming; Putcha, Preeti; Tetzlaff, Julie E.; Spoelgen, Robert; Koker, Mirjam; Carvalho, Filipe; Hyman, Bradley Theodore; McLean, Pamela June

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Citation: Outeiro, Tiago Fleming, Preeti Putcha, Julie E. Tetzlaff, Robert Spoelgen, Mirjam Koker, Filipe Carvalho, Bradley T. Hyman, and Pamela J. McLean. 2008. Formation of toxic oligomeric α-synuclein species in living cells. PLoS ONE 3(4).
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Abstract: Background: Misfolding, oligomerization, and fibrillization of α-synuclein are thought to be central events in the onset and progression of Parkinson's disease (PD) and related disorders. Although fibrillar α-synuclein is a major component of Lewy bodies (LBs), recent data implicate prefibrillar, oligomeric intermediates as the toxic species. However, to date, oligomeric species have not been identified in living cells. Methodology/Principal Findings: Here we used bimolecular fluorescence complementation (BiFC) to directly visualize α-synuclein oligomerization in living cells, allowing us to study the initial events leading to α-synuclein oligomerization, the precursor to aggregate formation. This novel assay provides us with a tool with which to investigate how manipulations affecting α-synuclein aggregation affect the process over time. Stabilization of α-synuclein oligomers via BiFC results in increased cytotoxicity, which can be rescued by Hsp70 in a process that reduces the formation of α-synuclein oligomers. Introduction of PD-associated mutations in α-synuclein did not affect oligomer formation but the biochemical properties of the mutant α-synuclein oligomers differ from those of wild type α-synuclein. Conclusions/Significance: This novel application of the BiFC assay to the study of the molecular basis of neurodegenerative disorders enabled the direct visualization of α-synuclein oligomeric species in living cells and its modulation by Hsp70, constituting a novel important tool in the search for therapeutics for synucleinopathies.
Published Version: doi://10.1371/journal.pone.0001867
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270899/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:4853333

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