Fibril Breaking Accelerates α-Synuclein Fibrillization

The formation of amyloid fibrils of alpha-synuclein (alpha Syn), the key protein in Parkinsons disease, is an autocatalytic process that is seeded by mature alpha Syn fibrils. Based on systematic measurements of the dependence of the fibril growth rate on the concentrations of monomers and preformed fibrillar seeds, we propose a mechanism of alpha Syn aggregation that includes monomer binding to fibril ends and secondary nucleation by fibril breaking. The model explains the increase of the alpha Syn aggregation rate under shaking conditions and the exponential increase in the fraction of fibrillar protein at the initial stages of alpha Syn aggregation. The proposed autocatalytic mechanism also accounts for the high variability in the aggregation lag time. The rate constant of monomer binding to the ends of fibrils, k(+) approximate to 1.3 mM(-1) s(-1), was estimated from the aggregation rate and previously reported average fibril lengths. From the aggregation rates at low concentrations the binding of monomeric alpha Syn to fibrils was found to be almost irreversible, with an equilibrium dissociation constant (K-d) smaller than 3 mu M.