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Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice
Open accessAbstract
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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“nearly all differential expression signatures from HD mice (35 of 37) (Langfelder et al., 2016) failed to overlap with microglial-enriched coexpression modules (Figure S5).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Langfelder et al., 2016
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Metadata
- 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
- Venue
- Nature Neuroscience
- Published
- 2016-02-22
- Volume
- 19
- Issue
- 4
- Pages
- 623-633
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- 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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