title: RAN Translation in Huntington Disease.
abstract: Huntington disease (HD) is caused by a CAG ⋅ CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other polyglutamine diseases.
authors.affiliation: Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Bañez-Coronel
authors.affiliation: Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Fatma
authors.initials: F
authors.lastname: Ayhan
authors.affiliation: Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Alex D
authors.initials: AD
authors.lastname: Tarabochia
authors.affiliation: Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zu
authors.affiliation: Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Perez
authors.affiliation: Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA; Genetics Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Solaleh Khoramian
authors.initials: SK
authors.lastname: Tusi
authors.affiliation: Department of Pathology, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
authors.affiliation: Division of Neurobiology, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Baltimore Huntington's Disease Center, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Division of Neurobiology, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Baltimore Huntington's Disease Center, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Yachnis
authors.affiliation: Department of Pathology, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA; Department of Neurology, University of Florida, Gainesville, FL 32610, USA; Genetics Institute, University of Florida, Gainesville, FL 32610, USA. Electronic address: ranum@ufl.edu.
authors.forename: Laura P W
authors.initials: LP
authors.lastname: Ranum
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D002531:Cerebellum / Q000378:metabolism; D002648:Child; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D014176:Protein Biosynthesis; D016372:RNA, Antisense / Q000235:genetics* / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D055815:Young Adult
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; D016372:RNA, Antisense; C019529:polyalanine; C027819:polyleucine; C027794:polyserine; C097188:polyglutamine; C057713:polycysteine