Physiological and Pathological Characterization of Alpha-Synuclein Oligomers

Abstract

α-Synuclein (αSyn) is highly abundant cytosolic protein whose conversion into insoluble fibrils is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Despite decades of research, fundamental questions regarding αSyn biology are unresolved. Soluble, prefibrillar oligomers, not their fibrillar end products, are believed to be neurotoxic in humans and in disease models, but their mechanism of action remains unknown. Evidence from our lab and others increasingly suggests that, in healthy cells, αSyn does not exist purely as an unfolded monomer, as the field has long believed, but also as aggregation-resistant, α-helical oligomers; however, their physiological role remains controversial. Thus, my aim was twofold: to characterize toxic αSyn species in the context of mitochondrial dysfunction, a central phenotypic feature of PD; and to purify helical αSyn oligomers from human brain to enable further characterization of physiological αSyn.