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Nat Neurosci. 2016 Apr;19(4):623-33. doi: 10.1038/nn.4256. Epub 2016 Feb 22.

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

Author information

1
Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
2
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
3
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
4
UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
6
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
7
Evotec Munich GmbH, Martinsried, Germany.
8
CHDI Foundation/CHDI Management Inc., Princeton, New Jersey, USA.
9
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
10
Department of Biostatistics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.

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.

PMID:
26900923
PMCID:
PMC5984042
DOI:
10.1038/nn.4256
[Indexed for MEDLINE]
Free PMC Article

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