title: Huntington's Disease Protein Huntingtin Associates with its own mRNA.
abstract: BACKGROUND
  The Huntington's disease (HD) protein huntingtin (Htt) plays a role in multiple cellular pathways. Deregulation of one or more of these pathways by the mutant Htt protein has been suggested to contribute to the disease pathogenesis. Our recent discovery-based proteomics studies have uncovered RNA binding proteins and translation factors associated with the endogenous Htt protein purified from mouse brains, suggesting a potential new role for Htt in RNA transport and translation.
  
  
  OBJECTIVE
  To investigate how Htt might affect RNA metabolism we set out to purify and analyze RNA associated with Htt.
  
  
  METHODS
  RNA was extracted from immunopurified Htt-containing protein complexes and analyzed by microarrays and RNA-Seq.
  
  
  RESULTS
  Surprisingly, the most enriched mRNA that co-purified with Htt was Htt mRNA itself. The association of Htt protein and Htt mRNA was detected independent of intact ribosomes suggesting that it is not an RNA undergoing translation. Furthermore, we identified the recently reported mis-spliced Htt mRNA encoding a truncated protein comprised of exon 1 and a portion of the downstream intron in the immunoprecipitates containing mutant Htt protein. We show that Htt protein co-localizes with Htt mRNA and that wild-type Htt reduces expression of a reporter construct harboring the Htt 3' UTR.
  
  
  CONCLUSIONS
  HD protein is found in a complex with its own mRNA and RNA binding proteins and translation factors. Htt may be involved in modulating its expression through post-transcriptional pathways. It is possible that Htt shares mechanistic properties similar to RNA binding proteins such as TDP-43 and FUS implicated in other neurodegenerative diseases.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Brady P
authors.initials: BP
authors.lastname: Culver
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: DeClercq
authors.affiliation: Genome Technology Center, New York University School of Medicine, New York, NY, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Dolgalev
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Man Shan
authors.initials: MS
authors.lastname: Yu
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.|Genome Technology Center, New York University School of Medicine, New York, NY, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tanese
mesh_terms: D000818:Animals; D002460:Cell Line; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism*; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D014793:Visual Cortex / Q000166:cytology
chemical_list: D000071058:Huntingtin Protein; D012333:RNA, Messenger
keywords: Fmrp; Huntington’s disease; RNA-protein interaction; huntingtin exon 1; mRNA translation