Conserved C-terminal charge exerts a profound influence on the aggregation rate of ?-synuclein.

ABSTRACT: ?-Synuclein (?-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, ?-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 ?-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 ?-syn variants. Comparison of the relative rates of aggregation reveals a strong monotonic relationship between the C-terminal charge of ?-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 ?-syn polymerization and may provide a target for the treatment of PD.

SUBMITTER: Levitan K 

PROVIDER: S-EPMC3143250 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature