Cited by 408Genetic Neurodegenerative DiseasesGenetics and Neurodevelopmental DisordersNeurological diseases and metabolism

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

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Langfelder, Peter, Cantle, Jeffrey P, Chatzopoulou, Doxa, Wang, Nan, Gao, Fuying, Al-Ramahi, Ismael, Lu, Xiao-Hong, Ramos, Eliana Marisa +14 more·2016·Nature Neuroscience

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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Authors
Langfelder, P., Cantle, J. P., Chatzopoulou, D., Wang, N., Gao, F., Al-Ramahi, I., Lu, X.-H., Ramos, E. M., El-Zein, K., Zhao, Y., Deverasetty, S., Tebbe, A., Schaab, C., Lavery, D. J., Howland, D., Kwak, S., Botas, J., Aaronson, J. S., Rosinski, J., Coppola, G., Horvath, S., & Yang, X. W.
Affiliations
  • University of California, Los Angeles (US)
  • Evotec (Germany) (DE)
  • CHDI Foundation (US)
  • Baylor College of Medicine (US)
Corresponding author
  • Horvath, Steve
  • Yang, X William
Venue
Nature Neuroscience
Published
2016-02-22
Volume
19
Issue
4
Pages
623-633
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W2274495055
Cited by
385
References
74
Citations by year
2026: 29 · 2025: 27 · 2024: 30 · 2023: 30 · 2022: 60 · 2021: 40 · 2020: 40 · 2019: 36 · 2018: 36 · 2017: 41 · 2016: 16
FWCI
19.76
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Hereditary Disease Foundation
  • CHDI Foundation
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS084298, R01NS049501, R01NS074312, P30NS062691)
  • Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
Huntington's disease, mutant huntingtin, CAG repeat length, repeat expansion, transcriptome, proteome, co-expression network, striatum, medium spiny neurons, cAMP signaling, protocadherins, cell death, age-related gene expression, disease-modifying genes, knock-in mice
MeSH terms
Huntingtin Protein, Animals, Cerebral Cortex, Corpus Striatum, Female, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Nuclear Proteins, Genomics, Proteomics, Mice, Gene Regulatory Networks, Gene Knock-In Techniques

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