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Neuroprotection by Histone Deacetylase-Related Protein
Abstract
The expression of histone deacetylase-related protein (HDRP) is reduced in neurons undergoing apoptosis. Forced reduction of HDRP expression in healthy neurons by treatment with antisense oligonucleotides also induces cell death. Likewise, neurons cultured from mice lacking HDRP are more vulnerable to cell death. Adenovirally mediated expression of HDRP prevents neuronal death, showing that HDRP is a neuroprotective protein. Neuroprotection by forced expression of HDRP is not accompanied by activation of the phosphatidylinositol 3-kinase-Akt or Raf-MEK-ERK signaling pathway, and treatment with pharmacological inhibitors of these pathways fails to inhibit the neuroprotection by HDRP. Stimulation of c-Jun phosphorylation and expression, an essential feature of neuronal death, is prevented by HDRP. We found that HDRP associates with c-Jun N-terminal kinase (JNK) and inhibits its activity, thus explaining the inhibition of c-Jun phosphorylation by HDRP. HDRP also interacts with histone deacetylase 1 (HDAC1) and recruits it to the c-Jun gene promoter, resulting in an inhibition of histone H3 acetylation at the c-Jun promoter. Although HDRP lacks intrinsic deacetylase activity, treatment with pharmacological inhibitors of histone deacetylases induces apoptosis even in the presence of ectopically expressed HDRP, underscoring the importance of c-Jun promoter deacetylation by HDRP-HDAC1 in HDRP-mediated neuroprotection. Our results suggest that neuroprotection by HDRP is mediated by the inhibition of c-Jun through its interaction with JNK and HDAC1.
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“HDAC inhibitors also demonstrate anti-inflammatory and neuroprotective effects in neurodegenerative models by dampening inflammatory signaling and supporting synaptic and cognitive function (Morrison et al., 2006; Zhou et al., 2018; Kumar et al., 2022).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Morrison et al., 2006
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Metadata
- Authors
- Morrison, B. E., Majdzadeh, N., Zhang, X., Lyles, A., Bassel-Duby, R., Olson, E. N., & D'Mello, S. R.
- Affiliations
- The University of Texas at Dallas (US)
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390
- The University of Texas Southwestern Medical Center (US)
- Department of Molecular and Cell Biology, University of Texas at Dallas, 2601 N. Floyd Rd., Richardson, Texas 75083
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-05-01
- Volume
- 26
- Issue
- 9
- Pages
- 3550-3564
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2024126284
- Cited by
- 100
- References
- 51
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 2 · 2016: 2 · 2015: 8 · 2014: 6 · 2013: 7 · 2012: 7
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS047201, R01NS040408, NS40408, R01NS047201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- neuroprotection, neuronal apoptosis, c-Jun phosphorylation, c-Jun N-terminal kinase, HDAC1, histone H3 acetylation, c-jun promoter, phosphatidylinositol 3-kinase/Akt signaling, MAPK/ERK pathway, antisense oligonucleotides, adenoviral gene expression, histone deacetylase inhibitors
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Cell Nucleus, Enzyme Inhibitors, Histone Deacetylases, Neurons, Phosphorylation, RNA, Messenger, Transcription, Genetic, Proto-Oncogene Proteins c-jun, Apoptosis, Phosphatidylinositol 3-Kinases, JNK Mitogen-Activated Protein Kinases, Extracellular Signal-Regulated MAP Kinases, Mice, Rats, Histone Deacetylase Inhibitors
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