The nuclear ubiquitin ligase adaptor SPOP is a conserved regulator of C9orf72 dipeptide toxicity

Abstract

Significance The G 4 C 2 repeat expansion in the C9orf72 gene is a major cause of frontotemporal dementia and amyotrophic lateral sclerosis. Unusual translation of the repeat sequence produces two highly toxic dipeptide repeat proteins (DPRs), PR X and GR X , which accumulate in the brain tissue of individuals with these diseases. Here, we show that PR and GR toxicity in both Caenorhabditis elegans and mammalian neurons depends on the E3 ubiquitin ligase adaptor SPOP . SPOP acts through bromodomain proteins to mediate dipeptide toxicity. SPOP inhibitors, which are currently being developed to treat SPOP -dependent renal cancer, also protect neurons against DPR toxicity. Our findings identify a highly conserved and “druggable” pathway that may represent a strategy for treating these currently incurable diseases.