Our studies use C. elegans as an animal model for Parkinson's disease (PD) to identify genetic factors which may impact this condition. PD is characterized by the degeneration of dopaminergic (DA) neurons and the formation of protein inclusions that contain the a-synuclein (a-syn) protein. Overexpression of human a-syn specifically in the eight DA neurons of C. elegans causes neurodegeneration in an age- and dose-dependent manner. The F16A11.2 gene product was found as one of several significant modifiers in an RNAi screen for functional effectors of a-syn toxicity (Hamamichi et al., 2008 PNAS). F16A11.2 is the worm homolog of the human HSPC117 protein (also identified as C22orf28) and shares approximately 75% sequence identity to its human homolog. Interestingly, HSPC117 was determined to be a component of RNA trafficking granules in neurons, along with other proteins, such as CGI-99 (an mRNA transcriptional modulator) and DDX1 (an RNA binding protein). Accordingly, HSPC117 has the ability to bind to AU-rich elements within mRNA. The RtcB domain in F16A11.2 is highly conserved and, based on studies of its bacterial homolog, could represent an uncharacterized RNA modification enzyme. Here, we show that overexpression of the F16A11.2 cDNA in DA neurons not only significantly protected these cells from a-syn neurotoxicity but also that neuronal-specific RNAi knockdown of this target results in enhanced neurodegeneration. Similar results were obtained when worms were exposed to the DA neurotoxin, 6-hydroxydopamine (6-OHDA). Result of yeast two-hybrid (Y2H) screen point to a possible interaction of the F16A11.2 protein with several cytoskeletal factors including actin (ACT-1) and alpha-tubulin (TBA-1). We conducted double knockdown studies between F16A11.2 and those Y2H hits that have been shown to be expressed in neurons and/or have an RNA binding domain, using dopamine neuron-specific RNAi. Our preliminary findings indicate genetic interaction with F59G1.4, a worm homolog of the ceramide glucosyltransferase, DDX-1 and
mir-2. As we continue to evaluate other positives from Y2H screening, we are also investigating the possible role of F16A11.2 in RNA trafficking by analyzing P granule localization. Collectively, these studies serve to illuminate the role of this evolutionarily conserved, but previously uncharacterized protein, coincident with the goal of uncovering new pathways associated with neuroprotection.