The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson's disease

Ronit Sharon, Ifat Bar-Joseph, Matthew P. Frosch, Dominic M. Walsh, James A. Hamilton, Dennis J. Selkoe

Research output: Contribution to journalArticlepeer-review

490 Scopus citations

Abstract

Accumulation of misfolded proteins as insoluble aggregates occurs in several neurodegenerative diseases. In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), α-synuclein (αS) accumulates in insoluble inclusions. To identify soluble αS oligomers that precede insoluble aggregates, we probed the cytosols of mesencephalic neuronal (MES) cells, normal and αS-transgenic mouse brains, and normal, PD, and DLB human brains. All contained highly soluble oligomers of αS whose detection was enhanced by delipidation. Exposure of living MES neurons to polyunsaturated fatty acids (PUFAs) increased αS oligomer levels, whereas saturated FAs decreased them. PUFAs directly promoted oligomerization of recombinant αS. Transgenic mice accumulated soluble oligomers with age. PD and DLB brains had elevated amounts of the soluble, lipid-dependent oligomers. We conclude that αS interacts with PUFAs in vivo to promote the formation of highly soluble oligomers that precede the insoluble αS aggregates associated with neurodegeneration.

Original languageAmerican English
Pages (from-to)583-595
Number of pages13
JournalNeuron
Volume37
Issue number4
DOIs
StatePublished - 20 Feb 2003
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Michael Schlossmacher for valuable comments and assistance. This work was supported by NIH grant NS 38375 (Morris K. Udall Center for Excellence in PD Research at Brigham and Women's Hospital).

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