RAN Translation in Huntington Disease

Monica Bañez-Coronel; Fatma Ayhan; Alex D Tarabochia; Tao Zu; Barbara A Perez; Solaleh Khoramian Tusi; Olga Pletnikova; David R Borchelt; Christopher A Ross; Russell L Margolis; Anthony T Yachnis; Juan C Troncoso; Laura P W Ranum

doi:10.1016/j.neuron.2015.10.038

RAN Translation in Huntington Disease

Neuron. 2015 Nov 18;88(4):667-77. doi: 10.1016/j.neuron.2015.10.038.

Affiliations

¹ Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
² 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.
³ Department of Pathology, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA.
⁵ 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.
⁶ 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.
⁷ Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
⁸ 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.
⁹ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged, 80 and over
Brain / metabolism*
Case-Control Studies
Cerebellum / metabolism
Child
Female
Frontal Lobe / metabolism
HEK293 Cells
Humans
Huntingtin Protein
Huntington Disease / genetics*
Huntington Disease / metabolism
Male
Middle Aged
Neostriatum / metabolism
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Peptides / metabolism
Protein Aggregation, Pathological / metabolism
Protein Biosynthesis
RNA, Antisense / genetics*
RNA, Antisense / metabolism
Trinucleotide Repeat Expansion / genetics*
Young Adult

Substances

HTT protein, human
Huntingtin Protein
Nerve Tissue Proteins
Peptides
RNA, Antisense
polyalanine
polyleucine
polyserine
polyglutamine
polycysteine

RAN Translation in Huntington Disease

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding