α-Synuclein misfolding and Parkinson's disease

Substantial evidence links alpha-synuclein, a small highly conserved presynaptic protein with unknown function, to both familial and sporadic Parkinson's disease (PD). alpha-Synuclein has been identified as the major component of Lewy bodies and Lewy neurites, the characteristic proteinaceous deposits that are the hallmarks of PD. alpha-Synuclein is a typical intrinsically disordered protein, but can adopt a number of different conformational states depending on conditions and cofactors. These include the helical membrane-bound form, a partially-folded state that is a key intermediate in aggregation and fibrillation, various oligomeric species, and fibrillar and amorphous aggregates. The molecular basis of PD appears to be tightly coupled to the aggregation of alpha-synuclein and the factors that affect its conformation. This review examines the different aggregation states of alpha-synuclein, the molecular mechanism of its aggregation, and the influence of environmental and genetic factors on this process. (C) 2011 Elsevier B.V. All rights reserved.