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

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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, 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·2016·Nature Neuroscience

DOI 10.1038/nn.4256PMC PMC5984042

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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
ORCID: Langfelder, Peter
Cantle, Jeffrey P
Wang, Nan
Gao, Fuying
Lu, Xiao-Hong
Ramos, Eliana Marisa
Zhao, Yining
Schaab, Christoph
Lavery, Daniel J
Howland, David
Kwak, Seung
Botas, Juan
Coppola, Giovanni
Horvath, Steve
Yang, X William
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2016-02-22
Volume: 19
Issue: 4
Pages: 623-633
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn.4256
PMC: PMC5984042
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: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
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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Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice

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