title: The aggregation and fibrillation of alpha-synuclein.
abstract: alpha-Synuclein is a small (14 kDa), abundant, intrinsically disordered presynaptic protein, whose aggregation is believed to be a critical step in Parkinson's disease (PD). The kinetics of alpha-synuclein fibrillation are consistent with a nucleation-dependent mechanism, in which the critical early stage of the structural transformation involves a partially folded intermediate. Although the basis for the toxic effects of aggregated alpha-synuclein are unknown, it has been proposed that transient oligomers are responsible, possibly by forming pores in membranes. In this Account, I discuss our investigations into the molecular basis for alpha-synuclein aggregation/fibrillation, including factors that either accelerate or inhibit fibrillation, effects of molecular crowding, oxidation, point mutations, and lipid membranes, as well as the variety of conformational and oligomeric states that alpha-synuclein can adopt. It is apparent that neuronal cells must have a very fine balance of factors that control the levels and potential aggregation of alpha-synuclein.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA. enzyme@cats.ucsc.edu
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Fink
mesh_terms: D001704:Biopolymers / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D018625:Microscopy, Atomic Force; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism; D011487:Protein Conformation; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D001704:Biopolymers; D051844:alpha-Synuclein