The many faces of α-synuclein: from structure and toxicity to therapeutic target

The abnormal accumulation of α-synuclein seems to have a central role in the pathophysiology of Parkinson's disease and related disorders. Masliah and colleagues review current knowledge regarding the conformational, oligomerization and aggregation states of this protein and how they influence α-synuclein function in health and disease. Disorders characterized by α-synuclein (α-syn) accumulation, Lewy body formation and parkinsonism (and in some cases dementia) are collectively known as Lewy body diseases. The molecular mechanism (or mechanisms) through which α-syn abnormally accumulates and contributes to neurodegeneration in these disorders remains unknown. Here, we provide an overview of current knowledge and prevailing hypotheses regarding the conformational, oligomerization and aggregation states of α-syn and their role in regulating α-syn function in health and disease. Understanding the nature of the various α-syn structures, how they are formed and their relative contributions to α-syn-mediated toxicity may inform future studies aiming to develop therapeutic prevention and intervention.