The Formation of Highly Soluble Oligomers of α-Synuclein Is Regulated by Fatty Acids and Enhanced in Parkinson's Disease

AbstractAccumulation 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