Yadav, M.; Harding, R. J.; Li, T.; Xu, X.; Gall-Duncan, T.; Khan, M.; Ferrari Bardile, C.; Sequiera, G. L.; Duan, S.; Chandrasekaran, R.; Pan, A.; Bu, J.; Yamazaki, T.; Hirose, T.; Prinos, P.; Tippett, L.; Turner, C.; Curtis, M. A.; Faull, R. L. M.; Pouladi, M. A.; Pearson, C. E.; He, H. H.; Arrowsmith, C. H.

The huntingtin protein, mutated in Huntington disease, is implicated in nucleic acid-mediated processes, yet evidence for direct huntingtin-nucleic acid interaction is limited. Here we show wildtype and mutant huntingtin co-purify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wildtype and mutant huntingtin revealed NEAT1 as a significantly enriched transcript. Altered NEAT1 levels were evident in Huntington disease cells and postmortem brain tissues, and huntingtin knockdown decreased NEAT1 levels. Huntingtin co-localized with NEAT1 in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights NEAT1 as a novel huntingtin interactor, demonstrating the involvement of huntingtin in RNA-mediated functions and paraspeckle regulation.