Huntingtin is an RNA binding protein that interacts with G-rich sequences, including those in the paraspeckle lncRNA NEAT1.
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
NEAT1
as a significantly enriched transcript. Altered
NEAT1
levels were evident in Huntington’s disease cells and postmortem brain tissues, and huntingtin knockdown decreased
NEAT1
levels. Huntingtin colocalized with
NEAT1
in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights
NEAT1
as a huntingtin interactor, demonstrating huntingtin’s involvement in RNA-mediated functions and paraspeckle regulation.
