Your browser doesn't support javascript.
loading
High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington's disease CAG knock-in mice across multiple genetic backgrounds.
Ament, Seth A; Pearl, Jocelynn R; Grindeland, Andrea; St Claire, Jason; Earls, John C; Kovalenko, Marina; Gillis, Tammy; Mysore, Jayalakshmi; Gusella, James F; Lee, Jong-Min; Kwak, Seung; Howland, David; Lee, Min Young; Baxter, David; Scherler, Kelsey; Wang, Kai; Geman, Donald; Carroll, Jeffrey B; MacDonald, Marcy E; Carlson, George; Wheeler, Vanessa C; Price, Nathan D; Hood, Leroy E.
Afiliação
  • Ament SA; Institute for Systems Biology, Seattle, WA, USA.
  • Pearl JR; Institute for Genome Sciences and Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
  • Grindeland A; Institute for Systems Biology, Seattle, WA, USA.
  • St Claire J; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA.
  • Earls JC; McLaughlin Research Institute, Great Falls, MT, USA.
  • Kovalenko M; Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
  • Gillis T; Institute for Systems Biology, Seattle, WA, USA.
  • Mysore J; Department of Computer Science, University of Washington, Seattle, WA, USA.
  • Gusella JF; Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
  • Lee JM; Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
  • Kwak S; Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
  • Howland D; Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
  • Lee MY; Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
  • Baxter D; CHDI Management/CHDI Foundation, Princeton, NJ, USA.
  • Scherler K; CHDI Management/CHDI Foundation, Princeton, NJ, USA.
  • Wang K; Institute for Systems Biology, Seattle, WA, USA.
  • Geman D; Institute for Systems Biology, Seattle, WA, USA.
  • Carroll JB; Institute for Systems Biology, Seattle, WA, USA.
  • MacDonald ME; Institute for Systems Biology, Seattle, WA, USA.
  • Carlson G; Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, USA.
  • Wheeler VC; Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
  • Price ND; Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
  • Hood LE; McLaughlin Research Institute, Great Falls, MT, USA.
Hum Mol Genet ; 26(5): 913-922, 2017 03 01.
Article em En | MEDLINE | ID: mdl-28334820
ABSTRACT
Huntington's disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+ mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Huntington / Corpo Estriado / Expansão das Repetições de Trinucleotídeos / Proteína Huntingtina Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Huntington / Corpo Estriado / Expansão das Repetições de Trinucleotídeos / Proteína Huntingtina Idioma: En Ano de publicação: 2017 Tipo de documento: Article