Transgenic C. elegans lines that over express human <font face=symbol>a</font>-synuclein A53T variant display uncoordinated movements (unc) and loss of dopaminergic neurons. Moreover, whole genome Affymetrix microarray studies have shown significant regulation of mitochodrial, proteasomal, and histone associated genes in these transgenic animals. We performed a RNA interference (RNAi) screen on genes residing on chromosome I, representing ~2300 RNAi clones, in order to identify suppressors or enhancers of the movement deficit phenotype in transgenic <font face=symbol>a</font>-synuclein A53T worms, as determined by a thrashing assay. Transgenic animals were sensitized to RNAi by genetic cross to an rrf-3
mutant. Twenty genes were found that significantly modified mobility in the assay. Ten suppressors of the phenotype, as determined by improved movement, included two peroxisomal genes (C47B2.8, W03D8.8) and the histone deacetylase hda-3
(R06C1.1). Ten enhancers, as determined by additional deficit of movement, included the myosin ortholog unc-15
(F07A5.7) and an actin binding protein (C45G3.1). Transgenic over expression of human <font face=symbol>a</font>-synuclein A53T in a hda-3
mutant background confirmed results observed in the RNAi screen. These results provide new avenues for investigation of the aetiology of movement disorders involving <font face=symbol>a</font>-synuclein and highlight the usefulness of C. elegans as a model organism for the study of human neurodegenerative diseases.