title: Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65.
abstract: Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Recent evidence suggests that HD is a consequence of multimodal, non-mutually exclusive mechanisms of pathogenesis that involve both HTT protein- and HTT RNA-triggered mechanisms. Here we provide further evidence for the role of expanded HTT (expHTT) RNA in HD by demonstrating that a fragment of expHTT is cytotoxic in the absence of any translation and that the extent of cytotoxicity is similar to the cytotoxicity of an expHTT protein fragment encoded by a transcript of similar length and with a similar repeat size. In addition, full-length (FL) expHTT is retained in the nucleus. Overexpression of the splicing factor muscleblind-like 1 (MBNL1) increases nuclear retention of expHTT and decreases the expression of expHTT protein in the cytosol. The splicing and nuclear export factor U2AF65 has the opposite effect, decreasing expHTT nuclear retention and increasing expression of expHTT protein. This suggests that MBNL1 and U2AF65 play a role in nuclear export of expHTT RNA.
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [2] Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Pan P
authors.initials: PP
authors.lastname: Li
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Cohen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Leonard O
authors.initials: LO
authors.lastname: Marque
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [3] Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [4] Program of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pulst
authors.affiliation: Laboratory of Drosophila Research, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Ho Yin Edwin
authors.initials: HY
authors.lastname: Chan
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [3] Program of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [2] Program of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Dobrila D
authors.initials: DD
authors.lastname: Rudnicki
mesh_terms: D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D018387:Codon, Initiator; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000378:metabolism*; D000072668:Splicing Factor U2AF; D019680:Trinucleotide Repeat Expansion
chemical_list: D018387:Codon, Initiator; C086055:HTT protein, human; D000071058:Huntingtin Protein; C493663:MBNL1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C000607494:U2AF2 protein, human