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Cited by 77Genetic Neurodegenerative DiseasesAmyotrophic Lateral Sclerosis ResearchGenetics and Neurodevelopmental Disorders

N17 Modifies Mutant Huntingtin Nuclear Pathogenesis and Severity of Disease in HD BAC Transgenic Mice

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Gu, Xiaofeng, Cantle, Jeffrey P., Greiner, Erin R., Lee, C.Y. Daniel, Barth, Albert M., Gao, Fuying, Park, Chang Sin, Zhang, Zhiqiang +6 more·2015·Neuron
DOI 10.1016/j.neuron.2015.01.008PMC PMC4386927
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Abstract

The nucleus is a critical subcellular compartment for the pathogenesis of polyglutamine disorders, including Huntington's disease (HD). Recent studies suggest the first 17-amino-acid domain (N17) of mutant huntingtin (mHTT) mediates its nuclear exclusion in cultured cells. Here, we test whether N17 could be a molecular determinant of nuclear mHTT pathogenesis in vivo. BAC transgenic mice expressing mHTT lacking the N17 domain (BACHD-ΔN17) show dramatically accelerated mHTT pathology exclusively in the nucleus, which is associated with HD-like transcriptionopathy. Interestingly, BACHD-ΔN17 mice manifest more overt disease-like phenotypes than the original BACHD mice, including body weight loss, movement deficits, robust striatal neuron loss, and neuroinflammation. Mechanistically, N17 is necessary for nuclear exclusion of small mHTT fragments that are part of nuclear pathology in HD. Together, our study suggests that N17 modifies nuclear pathogenesis and disease severity in HD mice by regulating subcellular localization of known nuclear pathogenic mHTT species.

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  • The BAC∆N17 mouse model contains wild type mouse Htt and mutant human HTT (97 CAG repeats) with 17 N-terminal amino acids removed.

    “This HD model contains wild type mouse Htt and mutant human HTT (97 CAG repeats) with 17 N-terminal amino acids removed31.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [31]

    The Introduction and Results describe BAC transgenic mice expressing human mutant HTT with 97Q on a mouse background. But the Results specify deletion of residues 2–16—15 amino acids within the N17 domain—not removal of all 17 N-terminal amino acids. (LLM, conf=0.90)

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References 64 · Cited by 77

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Authors
Gu, X., Cantle, J. P., Greiner, E. R., Lee, C. Y. D., Barth, A. M., Gao, F., Park, C. S., Zhang, Z., Sandoval-Miller, S., Zhang, R. L., Diamond, M., Mody, I., Coppola, G., & Yang, X. W.
Affiliations
  • University of California, Los Angeles (US)
  • Washington University in St. Louis (US)
Corresponding author
Yang, X. William
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2015-02
Volume
85
Issue
4
Pages
726-741
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2015.01.008
PMC
PMC4386927
OpenAlex
W2029399677
Cited by
77
References
64
Citations by year
2026: 4 · 2025: 8 · 2024: 6 · 2023: 8 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 11 · 2017: 10 · 2016: 11 · 2015: 1
FWCI
4.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc)
  • PubMed Central (acceptedVersion, cc-by-nc)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
Funders
National Institute of Neurological Disorders and Stroke (R01NS084298, R01NS049501, R01NS074312, P30NS062691, T32NS048004)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Huntington's disease, mutant huntingtin, nuclear exclusion, polyglutamine diseases, BACHD mice, neuroinflammation, disease severity, subcellular localization
MeSH terms
Huntingtin Protein, Age Factors, Animals, Brain, Cell Nucleolus, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Huntington Disease, Locomotion, Male, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Organ Size, Phenotype, Subcellular Fractions, Protein Structure, Tertiary, Trinucleotide Repeat Expansion, Mice, HEK293 Cells

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