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PLoS One. 2008 Apr 2;3(4):e1867. doi: 10.1371/journal.pone.0001867.

Formation of toxic oligomeric alpha-synuclein species in living cells.

Author information

1
Alzheimer's Research Unit, MassGeneral Institute for Neurodegenerative Disease, MGH Harvard Medical School, Charlestown, Massachusetts, United States of America. touteiro@fm.ul.pt

Erratum in

  • PLoS One. 2008;3(5). doi: 10.1371/annotation/9282f173-df82-4b70-9120-b4e62b3dacb1.

Abstract

BACKGROUND:

Misfolding, oligomerization, and fibrillization of alpha-synuclein are thought to be central events in the onset and progression of Parkinson's disease (PD) and related disorders. Although fibrillar alpha-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 alpha-synuclein oligomerization in living cells, allowing us to study the initial events leading to alpha-synuclein oligomerization, the precursor to aggregate formation. This novel assay provides us with a tool with which to investigate how manipulations affecting alpha-synuclein aggregation affect the process over time. Stabilization of alpha-synuclein oligomers via BiFC results in increased cytotoxicity, which can be rescued by Hsp70 in a process that reduces the formation of alpha-synuclein oligomers. Introduction of PD-associated mutations in alpha-synuclein did not affect oligomer formation but the biochemical properties of the mutant alpha-synuclein oligomers differ from those of wild type alpha-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 alpha-synuclein oligomeric species in living cells and its modulation by Hsp70, constituting a novel important tool in the search for therapeutics for synucleinopathies.

PMID:
18382657
PMCID:
PMC2270899
DOI:
10.1371/journal.pone.0001867
[Indexed for MEDLINE]
Free PMC Article

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