HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration
Open accessAbstract
Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine-rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor coordination, neurological phenotypes, and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics.
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Cytoplasmic HDAC4 may have neuroprotective effects.
“HDAC4 in the cytoplasm may have neuroprotective effects.145–147”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [147]
The Discussion reports the opposite effect in Huntington’s disease mouse models: reducing HDAC4 delayed cytoplasmic aggregation, restored synaptic function, and improved neurological outcomes. It describes the relevant cytoplasmic mechanism as contributing to neurodegeneration, not as neuroprotective. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredInhibiting HDAC4 delayed huntingtin protein cytoplasmic aggregate formation, restored BDNF transcript levels, and restored neuronal and cortico-striatal synaptic function in mouse models of neurological disorders.
“Inhibiting HDAC4 delayed the formation of huntingtin protein cytoplasmic aggregates, while the levels of BDNF transcripts were restored, resulting in the restoration of neuronal and cortico-striatal synaptic function in mouse models of neurological disorders.147”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [147]
The Results report that HDAC4 reduction almost restored dysregulated Bdnf transcripts in R6/2 mice, and the Introduction reports delayed cytoplasmic huntingtin aggregation and improved neuronal membrane properties and corticostriatal transmission. The claim extends these findings from Huntington’s disease mouse models to mouse models of neurological disorders generally. The paper also does not establish that restored Bdnf transcripts caused the synaptic improvement. (LLM, conf=0.85)
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- Authors
- Mielcarek, M., Landles, C., Weiss, A., Bradaia, A., Seredenina, T., Inuabasi, L., Osborne, G. F., Wadel, K., Touller, C., Butler, R., Robertson, J., Franklin, S. A., Smith, D. L., Park, L., Marks, P. A., Wanker, E. E., Olson, E. N., Luthi-Carter, R., van der Putten, H., Beaumont, V., & Bates, G. P.
- Affiliations
- King's College London (GB)
- Novartis (Switzerland) (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- CHDI Foundation (US)
- Memorial Sloan Kettering Cancer Center (US)
- Max Delbrück Center (DE)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Bates, Gillian P.
- ORCID
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-11-26
- Volume
- 11
- Issue
- 11
- Pages
- e1001717
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC3841096
- OpenAlex
- W2100574142
- Cited by
- 172
- References
- 66
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 11 · 2023: 9 · 2022: 12 · 2021: 14 · 2020: 14 · 2019: 10 · 2018: 12 · 2017: 12 · 2016: 16 · 2015: 21 · 2014: 23 · 2013: 2
- FWCI
- 10.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- CHDI Foundation
- King's College London
- Deutsche Forschungsgemeinschaft (SFB618, SFB740)
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- HDAC4, Huntington's disease, huntingtin, polyglutamine expansion, cytoplasmic aggregation, protein aggregation, brain-derived neurotrophic factor, corticostriatal synapses, motor coordination, lifespan, small molecule drugs, glutamine-rich domain
- MeSH terms
- Huntingtin Protein, Animals, Cerebral Cortex, Female, Histone Deacetylases, Huntington Disease, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Nerve Tissue Proteins, Synaptic Transmission, Neurons, Nuclear Proteins, Phenotype, Transcription, Genetic, Mice, Knockout, Brain-Derived Neurotrophic Factor, Epigenesis, Genetic, Rotarod Performance Test, Mice, Gene Knockdown Techniques, Mice, 129 Strain
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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