Alpha-synuclein structure and Parkinson's disease - lessons and emerging principles

Alpha-synuclein (alpha S) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). All diseases are determined by alpha S aggregate deposition but can be separated into distinct pathological phenotypes and diagnostic criteria. Here we attempt to reinterpret the literature, particularly in terms of how alpha S structure may relate to pathology. We do so in the context of a rapidly evolving field, taking into account newly revealed structural information on both native and pathogenic forms of the alpha S protein, including recent solid state NMR and cryoEM fibril structures. We discuss how these new findings impact on current understanding of alpha S and PD, and where this information may direct the field.