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

Nature Neuroscience
Peter LangfelderX William Yang

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.

Associated Datasets

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Citations

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Datasets Mentioned

BETA
PXD003442

Methods Mentioned

BETA
RNA-seq
genotyping
Chip-Seq
transgenic
Assay
acetylation
PCR

Software Mentioned

R package preprocessCore
STAR
Sample Network
MaxQuant
HTSeq
Bioconductor package
WGCNA
MaxLFQ
Allen Brain Atlas ( ABA
R

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