Parkinson''s disease (PD) is the second most common neurodegenerative disorder. Studies of familial forms of PD have identified genes that when mutated or over-expressed, result in enhanced susceptibility to dopamine (DA) neurodegeneration. One of these proteins, alpha-synuclein (a-syn), has been shown to aggregate and form protein inclusion bodies. Overexpression of human a-syn in C. elegans resulted in accumulation of this protein and was used to screen for effectors of age-dependent aggregrate formation in vivo. Using RNAi, our lab has identified several genes that, when knocked down, increase aggregate formation within the body wall muscles. Notably, overexpressing several of these effector proteins in worm DA neurons led to protection from a-syn-induced neurodegeneration (Hamamichi et al. 2008, PNAS). Of these neuroprotective proteins, a lysosomal trafficking protein, VPS-41, was the most effective at preventing neurodegeneration. VPS41 is a highly conserved protein expressed in mammalian DA neurons. It has metal ion binding, clathrin CLH, RING finger, and AP3 interaction domains, and has been shown to be involved in lysosomal trafficking in yeast. To identify domains of VPS41 responsible for its neuroprotective actions, we truncated different domains of human VPS41 and overexpressed these truncates in a-syn-expressing DA neurons of worms. Select truncated forms of VPS41 exhibited DA neuroprotection against a-syn-induced degeneration, with the clathrin CLH and AP3 interaction domains being the common domains between the protective isoforms. This neuroprotection by VPS41 was not seen in an AP3 mutant background or when the clathrin CLH domain was mutated with a SNP (C647R). Furthermore, VPS41 overexpressing worms also showed resistance to 6-OHDA induced DA degeneration, indicating VPS41 can protect against different forms of cellular stresses associated with modeling PD in vivo. Importantly, the neuroprotective capacity of VPS41 extends to mammalian cellular models where SH-SY5Y neuroblastoma cells transfected with human VPS41 exhibit protection from a broad kinase inhibitor, staurosporine; the PD-related neurotoxin, rotenone; and the oxidative stress inducer, 6-OHDA. The presence of VPS41 in these cells significantly reduces the sensitivity of the lines to all three toxins. These data demonstrate that VPS41 is part of an evolutionarily conserved mechanism that is neuroprotective in both mammalian cells and C. elegans. Thus, the VPS41 protein and, by extension, the regulation of autophagy, represents a promising target for therapeutic development against PD.