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We transfected neuroblastoma cells with WT α-syn and α-syn mutants A53T and E46K to compare their effects on the promotion of neurite outgrowth. In contrast to WT and A53T α-syn transfectants, E46K α-syn transfectants negatively regulated neurite outgrowth. Furthermore, the expression of Cdc42EP2 protein was suppressed by E46K α-syn, leading to decreased βIII-tubulin levels, which was opposite to the effect of WT and A53T α-syn. Importantly, E46K α-syn is the first α-syn mutant reported to inhibit neurite outgrowth rather than promote it, as is the case with WT α-syn and other α-syn mutants. Our findings provide insight into the biological function and pathogenic mechanisms of α-syn and may lead to the identification of novel targets for the development of therapeutics for PD that reduce α-syn levels.