Transient Receptor Potential (TRP) channels are conserved across phylogeny and function as polymodal cellular sensors. Numerous mutations have been shown to affect TRP channel function, causing inherited channelopathies, a rapidly expanding group of neurological disorders. Furthermore, the role of TRP channels in calcium signaling and homeostasis has implicated them in neurodegenerative disease, including Parkinson's. Here, we use a model of dopaminergic degeneration in Caenorhabditis elegans, in which a dominant mutation in a Transient Receptor Potential (TRP) channel, TRP-4, results in a hyperactive channel state. Consequently, this mutation leads to a progressive and robust loss of dopaminergic neurons through calcium dyshomeostasis. Gain-of-function mutations in ion channels with easily detectable phenotypes such as neurodegeneration, offer a unique opportunity to identify neuroprotective genes, including genes that are important for channel function. We performed a forward genetic screen for suppressors of dopaminergic neuronal loss and retrieved a collection of mutant strains that show neuroprotection from
trp-4(d)-induced degeneration. We identified the causal mutations using whole-genome sequencing. Here we present neuroprotective mutations that affect components of the secretory pathway. Specifically, we identified a nonsense and a missense allele of
cni-1, the only Cornichon ortholog in C. elegans, that fully suppress neuronal cell death. Cornichon is a cargo receptor that couples specific membrane proteins to the COPII vesicle-coat, regulating their export from the ER. In addition, we recovered two viable missense mutations in the COPII coat adapter protein SEC-24.2, which act in a dominant manner to suppress neurodegeneration. We find that the above mutations alter TRP-4 channel trafficking, reducing the amount present at the membrane and impairing its localization to the cilium. We are testing the retrieved mutations for their specificity in affecting trafficking and localization of other members of the TRP channel family. Overall, our results indicate that we have identified a two-component ER-export mechanism for the TRP-4 channel, which may also be relevant for regulating trafficking of other members of the TRP channel family. The identified mutations reveal potential interaction points between the TRP-4 cargo, the cargo receptor CNI-1, and SEC-24.2.