Ribosome collisions on expanded polyQ trigger cell dysfunction in Huntington's Disease

Huntington's Disease (HD) is a neurodegenerative disorder caused by CAG repeat expansions in Huntingting (Htt), encoding an aggregation-prone polyglutamine (polyQ) tract. How such expansions lead to disease remains unclear. Here we show that they profoundly affect translation of Htt mRA. We find that Htt translation initiation is inhibited by an upstream open reading frame (uORF) and induced by eIF2a phosphorylation during stress and differentiation. Higher rates of initiation lead to higher risk of ribosome collisions on CAG expansions. Analyses in cell and animal models of HD show that mutant Htt depletes elongation factor eIF5A, required to resolve such collisions. Loss of eIF5A causes widespread ribosome stalling throughout the translatome, resulting in chronic ribotoxicity, aberrant response to acute stress and defects in ribosome and proteasome assembly. We propose that ribosome collisions linked to polyQ expansion are a key mediator of dysfunction in HD and an important target for therapeutic intervention.