The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?
Abstract
Histone deacetylase (HDAC) family members are important mediators of epigenetic mechanisms in the regulation of memory formation. Recent studies have revealed that Class IIa HDAC family member HDAC4 contributes essential functions to synaptic plasticity and memory as well as other neurological processes. HDAC4 is localized to both the nucleus and cytoplasm and undergoes subcellular shuttling in response to synaptic activity. In the nucleus, HDAC4 is a repressor of transcriptional programmes, although vertebrate HDAC4 is itself catalytically inactive and repression is facilitated through direct inhibition of transcription factors such as MEF2. In the brain, however, HDAC4 is predominantly cytoplasmic, and a pool of HDAC4 is concentrated in dendritic spines. This review explores and synthesizes the evidence that specific subcellular pools of HDAC4 mediate differential effects on neurological function. Nuclear-restriction of HDAC4 results in down-regulation of plasticity-related genes and memory impairment. However loss of HDAC4 also results in memory deficits through unknown mechanisms. The localization to dendritic shafts and spines, combined with the evidence that cytoplasmic HDAC4 is neuroprotective in some models of neurological dysfunction point to an essential cytoplasmic role. Investigation of extra-nuclear roles of HDAC4, including identification of cytoplasmic binding partners is paramount in order to understand and therefore manipulate its function for potential therapeutic benefit.
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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 [145]
Cites
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Yuan, M., Yang, B., Rothschild, G., Mann, J. J., Sanford, L. D., Tang, X., Huang, C., Wang, C., & Zhang, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01519-z · Cited by 246 · see citing works
“145 – 147 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.”
Background
- Authors
- Fitzsimons, H. L.
- Affiliations
- Massey University (NZ)
- Corresponding author
- Fitzsimons, Helen L.
- ORCID
- Fitzsimons, Helen L.
- Venue
- Neurobiology of Learning and Memory
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 123
- Pages
- 149-158
- ISSN
- 1074-7427 (ISSN-L)
- OpenAlex
- W565347010
- Cited by
- 41
- References
- 10
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 5 · 2021: 2 · 2020: 2 · 2019: 9 · 2018: 3 · 2017: 1 · 2016: 9
- FWCI
- 0.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Learning and Memory (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Massey University
- Health Research Council of New Zealand
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- HDAC4, class IIa histone deacetylases, nuclear localization, dendritic spines, synaptic plasticity, memory formation, MEF2, transcriptional repression, neuroprotection, epigenetic regulation
- MeSH terms
- Animals, Brain, Cytoplasm, Histone Deacetylases, Humans, Memory, Neuronal Plasticity, Neurons, Repressor Proteins
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