Altered Fatty Acid Composition of Dopaminergic Neurons Expressing α-Synuclein and Human Brains with α-Synucleinopathies

Abstract

α-Synuclein (αS) is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson's disease (PD) and the related disorder, dementia with Lewy bodies (DLB). A central question about the role of αS in the pathogenesis of PD and DLB concerns how this normally soluble protein assembles into insoluble aggregates associated with neuronal dysfunction. We recently detected highly soluble oligomers of αS in normal brain supernatants and observed their augmentation in PD and DLB brains. Further, we found that polyunsaturated fatty acids (PUFAs) enhanced αS oligomerization in intact mesencephalic neuronal cells. We now report the presence of elevated PUFA levels in PD and DLB brain soluble fractions. Higher PUFA levels were also detected in the supernatants and high-speed membrane fractions of neuronal cells over-expressing wild-type or PD-causing mutant αS. This increased PUFA content in the membrane fraction was accompanied by increased membrane fluidity in the αS overexpressing neurons. In accord, membrane fluidity and the levels of certain PUFAs were decreased in the brains of mice genetically deleted of αS. Together with our earlier observations, these results suggest that αS-PUFA interactions help regulate neuronal PUFA levels as well as the oligomerization state of αS, both normally and in human synucleinopathies.