HDAC6 is a target for protection and regeneration following injury in the nervous system
Open accessAbstract
Central nervous system (CNS) trauma can result in tissue disruption, neuronal and axonal degeneration, and neurological dysfunction. The limited spontaneous CNS repair in adulthood and aging is often insufficient to overcome disability. Several investigations have demonstrated that targeting HDAC activity can protect neurons and glia and improve outcomes in CNS injury and disease models. However, the enthusiasm for pan-HDAC inhibition in treating neurological conditions is tempered by their toxicity toward a host of CNS cell types –a biological extension of their anticancer properties. Identification of the HDAC isoform, or isoforms, that specifically mediate the beneficial effects of pan-HDAC inhibition could overcome this concern. Here, we show that pan-HDAC inhibition not only promotes neuronal protection against oxidative stress, a common mediator of injury in many neurological conditions, but also promotes neurite growth on myelin-associated glycoprotein and chondroitin sulfate proteoglycan substrates. Real-time PCR revealed a robust and selective increase in HDAC6 expression due to injury in neurons. Accordingly, we have used pharmacological and genetic approaches to demonstrate that inhibition of HDAC6 can promote survival and regeneration of neurons. Consistent with a cytoplasmic localization, the biological effects of HDAC6 inhibition appear transcription-independent. Notably, we find that selective inhibition of HDAC6 avoids cell death associated with pan-HDAC inhibition. Together, these findings define HDAC6 as a potential nontoxic therapeutic target for ameliorating CNS injury characterized by oxidative stress-induced neurodegeneration and insufficient axonal regeneration.
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Selective inhibition of HDAC6 by small molecule or genetic tools promotes survival and re-growth of neurons following injury.
“Selective inhibition of HDAC6 by small molecule or genetic tools has been demonstrated to promote survival and re-growth of neurons following injury, offering the possibility for pharmacological intervention in both CNS injury and neurodegenerative conditions.19”
From Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A (2010) · cites this paper as [19]
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- Authors
- Rivieccio, M. A., Brochier, C., Willis, D. E., Walker, B. A., D'Annibale, M. A., McLaughlin, K., Siddiq, A., Kozikowski, A. P., Jaffrey, S. R., Twiss, J. L., Ratan, R. R., & Langley, B.
- Affiliations
- Cornell University (US)
- Alfred I. duPont Hospital for Children (US)
- Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605;
- Burke Medical Research Institute (US)
- University of Illinois Chicago (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-11-17
- Volume
- 106
- Issue
- 46
- Pages
- 19599-19604
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2780768
- OpenAlex
- W2034859720
- Cited by
- 322
- References
- 40
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 17 · 2023: 29 · 2022: 10 · 2021: 17 · 2020: 29 · 2019: 24 · 2018: 21 · 2017: 20 · 2016: 19 · 2015: 24 · 2014: 21 · 2013: 25 · 2012: 13
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS056306, R01NS049041)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- HDAC6, histone deacetylase inhibition, central nervous system injury, axon regeneration, oxidative stress, neuroprotection, neuronal survival, myelin-associated glycoprotein, chondroitin sulfate proteoglycans, neurodegeneration
- MeSH terms
- Histone Deacetylase 6, Animals, Central Nervous System, Cerebral Cortex, Ganglia, Spinal, Histone Deacetylases, Male, Nerve Regeneration, Neurons, Neurites, Rats, Sprague-Dawley, Apoptosis, Oxidative Stress, Neurodegenerative Diseases, RNA Interference, Rats
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