Huntingtin is an RNA binding protein and participates in <i>NEAT1</i>-mediated paraspeckles.

Abstract

Huntingtin protein, mutated in Huntington's disease, is implicated in nucleic acid-mediated processes, yet the evidence for direct huntingtin-nucleic acid interaction is limited. Here, we show wild-type and mutant huntingtin copurify 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 wild-type and mutant huntingtin revealed long noncoding RNA <i>NEAT1</i> as a significantly enriched transcript. Altered <i>NEAT1</i> levels were evident in Huntington's disease cells and postmortem brain tissues, and huntingtin knockdown decreased <i>NEAT1</i> levels. Huntingtin colocalized with <i>NEAT1</i> in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights <i>NEAT1</i> as a huntingtin interactor, demonstrating huntingtin's involvement in RNA-mediated functions and paraspeckle regulation.