Fibril
Breaking Accelerates α‑Synuclein
Fibrillization
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Abstract
The formation of amyloid fibrils
of α-synuclein (αSyn),
the key protein in Parkinson’s disease, is an autocatalytic
process that is seeded by mature αSyn 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 αSyn aggregation that includes monomer binding to fibril
ends and secondary nucleation by fibril breaking. The model explains
the increase of the αSyn aggregation rate under shaking conditions
and the exponential increase in the fraction of fibrillar protein
at the initial stages of αSyn 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, <i>k</i><sub><i>+</i></sub> ≈ 1.3 mM<sup>–1</sup> s<sup>–1</sup>, was estimated from the aggregation rate and
previously reported average fibril lengths. From the aggregation rates
at low concentrations the binding of monomeric αSyn to fibrils
was found to be almost irreversible, with an equilibrium dissociation
constant (<i>K</i><sub>d</sub>) smaller than 3 μM