While mutant htt has been proposed to exert its toxicity through various mechanisms including transcriptional dysregulation [2] and disturbances to protein folding networks [3], the finding that htt inclusion bodies are polyubiquitylated in transgenic mice and HD patient brains has long suggested that altered ubiquitin homeostasis or impaired ubiquitin-proteasome system (UPS)-dependent protein degradation may contribute to HD pathology [1], [4]. The gene discussed is HTT; the disease is Huntington disease.