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Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.
Langfelder, Peter; Cantle, Jeffrey P; Chatzopoulou, Doxa; Wang, Nan; Gao, Fuying; Al-Ramahi, Ismael; Lu, Xiao-Hong; Ramos, Eliana Marisa; El-Zein, Karla; Zhao, Yining; Deverasetty, Sandeep; Tebbe, Andreas; Schaab, Christoph; Lavery, Daniel J; Howland, David; Kwak, Seung; Botas, Juan; Aaronson, Jeffrey S; Rosinski, Jim; Coppola, Giovanni; Horvath, Steve; Yang, X William.
Afiliação
  • Langfelder P; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
  • Cantle JP; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
  • Chatzopoulou D; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
  • Wang N; UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
  • Gao F; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
  • Al-Ramahi I; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
  • Lu XH; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
  • Ramos EM; UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
  • El-Zein K; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
  • Zhao Y; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
  • Deverasetty S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Tebbe A; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
  • Schaab C; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
  • Lavery DJ; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
  • Howland D; UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
  • Kwak S; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
  • Botas J; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
  • Aaronson JS; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Rosinski J; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
  • Coppola G; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
  • Horvath S; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
  • Yang XW; Evotec Munich GmbH, Martinsried, Germany.
Nat Neurosci ; 19(4): 623-33, 2016 Apr.
Article em En | MEDLINE | ID: mdl-26900923
ABSTRACT
To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Nucleares / Genômica / Proteômica / Redes Reguladoras de Genes / Proteínas do Tecido Nervoso Limite: Animals Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Nucleares / Genômica / Proteômica / Redes Reguladoras de Genes / Proteínas do Tecido Nervoso Limite: Animals Idioma: En Ano de publicação: 2016 Tipo de documento: Article