Bent out of shape: α-Synuclein misfolding and the convergence of pathogenic pathways in Parkinson's disease

Protein inclusions made up primarily of misfolded alpha-synuclein (alpha-Syn) are the hallmark of a set of disorders known as synucleinopathies, most notably Parkinson's disease (PD). It is becoming increasingly appreciated that alpha-Syn misfolding can spread to anatomically connected regions in a prion-like manner. The protein aggregates that ensue are correlated with neurodegeneration in the various yet select neuronal populations that are affected. Recent advances have begun to shed light on the spreading and toxicity mechanisms that may be occurring in PD. Several key emerging themes are arising from this work suggesting that alpha-Syn mediated neurodegeneration is due to a combination of relative alpha-Syn expression level, connectivity to affected brain regions, and intrinsic vulnerability to pathology. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.