Alpha‐Synuclein

Abstract α‐Synuclein (αS) is a presynaptic small protein that has attracted much interest because its aggregation and accumulation in the form of amyloid fibrils is the hallmark of a range of neurodegenerative disorders, collectively referred to as synucleinopathies. Despite intense research on this protein since it was first identified two decades ago as the major component of the proteinaceous intracellular inclusion characteristics of Parkinson disease, there is still no consensus on the physiological function of the protein and much remains to be established on the molecular basis of its toxicity. Recently, important steps have been undertaken to identify the different conformational states that this protein is able to adopt and elucidate their role in physiological and pathological conditions. Key Concepts The physiological function(s) of α‐synuclein remains controversial, although recent evidences suggest a major regulatory role in synapsis. At physiological conditions, α‐synuclein is in a dynamic equilibrium between a membrane‐bound α‐helical (likely multimeric) conformation and a cytosolic intrinsically disordered (monomeric) conformation. α‐Synuclein aggregation and fibril formation likely play a central role in Parkinson disease and other neurodegenerative disorders. Different strains or fibril polymorphs of α‐synuclein have different degrees of infectivity and might be associated with distinct types of pathologies. Different mechanisms of formation of α‐synuclein amyloid aggregates have been observed in vitro , but their relative relevance in vivo remains unknown. Recent studies support the idea that multiple aggregated species of α‐synuclein can be generated through diverse misfolding pathways during the process of amyloid aggregation and could play distinct roles during the development of disease. Combined methods to target specifically different α‐synuclein conformations could potentially prevent α‐synuclein‐associated toxicity.