Residual structure and dynamics in Parkinson's disease-associated mutants of alpha-synuclein

alpha -Synuclein (alphaS) is a pre-synaptic protein that has been implicate d as a possible causative agent in the pathogenesis of Parkinson's disease (PD). Two autosomal dominant missense mutations in the aS gene are associat ed with early onset PD. Because aS is found in an aggregated fibrillar form in the Lewy body deposits characteristic of Parkinson's patients, aggregat ion of the protein is believed to be related to its involvement in the dise ase process. The wild type (WT) and early onset mutants A30P and A53T displ ay diverse in vitro aggregation kinetics even though the gross physicochemi cal and morphological properties of the mutants are highly similar. We used high resolution solution NMR spectroscopy to compare the structural and dy namic properties of the A53T and A30P mutants with those of WT aS in the fr ee state. We found that the A30P mutation disrupts a region of residual hel ical structure that exists in the WT protein, whereas the A53T mutation res ults in a slight enhancement of a small region around the site of mutation with a preference for extended conformations. Based on these results and on the anticipated effects of these mutations on elements of secondary struct ure, we proposed a model of how these two PD-linked mutations influence aS fibril formation that is consistent with the documented differences in the fibrillization kinetics of the two mutants.