cnnm-5 knockdown improves proteostasis of mutant Huntingtin protein in C. elegans

Huntington's disease (HD) is an age-related neurodegenerative disease associated with the aggregation of mutant Huntingtin protein (mHTT). It is theorized that prevention or clearance of these aggregates through autophagy and the ubiquitin proteasome system (UPS) protects neurons from degeneration. Using a C. elegans model of HD, a small reverse genetic screen of 100 random genes on Chromosome 3 identified cnnm-5 as a genetic modifier of mHTT accumulation. During development, loss of cnnm-5 by RNAi ( cnnm-5 i) protects against mHTT accumulation, implicating cnnm-5 as a negative regulator of protein aggregation prevention or clearance. Here we report that knocking down cnnm-5 leads to decreased mHTT protein aggregation through the upregulation of the UPS and autophagy pathways, leading to increased lifespan. Further experimentation using a nematode model of Alzheimer's disease demonstrates cnnm-5 i protects against paralysis by decreasing beta amyloid protein misfolding in body wall muscles.