biostudies-literatureBanez-Coronel MNIA NIH HHSNINDS NIH HHS667-77https://www.ebi.ac.uk/biostudies/studies/S-EPMC4684947biostudies-literatureUnknown88(4)Huntington disease (HD) is caused by a CAG ⋅ CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic stratNeuronRAN Translation in Huntington Disease.PMC4684947P50 AG005146NS082168P50AG05146T32 NS082168R37 NS040389Margolis RLZu TYachnis ATBanez-Coronel MPerez BABorchelt DRPletnikova OTroncoso JCRoss CAAyhan FTusi SKRanum LPTarabochia ADfalseRAN Translation in Huntington Disease.Huntington disease (HD) is caused by a CAG ⋅ CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strat2015-01-01T00:00:00Z2015 Nov2025-04-22T11:47:32.589Z2019-03-27T02:05:29ZS-EPMC46849472659034410.1016/j.neuron.2015.10.038