Conserved C-Terminal Charge Exerts a Profound Influence on the Aggregation Rate of α-Synuclein

alpha-Synuclein (alpha-syn) is the major component of filamentous Lewy bodies found in the brains of patients diagnosed with Parkinson's disease (PD). Recent studies demonstrate that, in addition to the wild-type sequence, alpha-syn is found in several modified forms, including truncated and phosphorylated species. Although the mechanism by which the neuronal loss in PD occurs is unknown, aggregation and fibril formation of alpha-syn are considered to be key pathological features. In this study, we analyze the rates of fibril formation and the monomer fibril equilibrium for eight disease-associated truncated and phosphorylated alpha-syn variants. Comparison of the relative rates of aggregation reveals a strong monotonic relationship between the C-terminal charge of alpha-syn and the lag time prior to the observation of fibril formation, with truncated species exhibiting the fastest aggregation rates. Moreover, we find that a decrease in C-terminal charge shifts the equilibrium to favor the fibrillar species. An analysis of these findings in the context of linear growth theories suggests that the loss of the charge-mediated stabilization of the soluble state is responsible for the enhanced aggregation rate and increased extent of fibril fraction. Therefore, C-terminal charge is kinetically and thermodynamically protective against alpha-syn polymerization and may provide a target for the treatment of PD. (C) 2011 Elsevier Ltd. All rights reserved.