Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia
Open accessAbstract
Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.
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Nuclear HDAC4 functions as a transcriptional repressor, downregulating plasticity-related genes, and may mediate learning and memory impairment in mice.
“Nuclear HDAC4 functions as a transcriptional repressor, downregulating the expression of numerous plasticity-related genes, that may mediate effects on learning and memory impairment in mice.143,144”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [144]
The Results section, “Nuclear HDAC4 suppresses neuronal gene expression driving neurodegenerative events” (page unavailable), reports reduced transcription of neuronal genes including Bdnf, NR2a and Nrxn in Atm−/− mice. The Discussion describes nuclear HDAC4 as a participant in transcriptional suppression. The mouse behavioral tests measured motor performance and exploratory activity, not learning or memory impairment, so that part of the claim is not supported by this paper. (LLM, conf=0.88)
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Cites
The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041 · see citing works
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage
Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R., Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y., et al. (2007) · Science · doi:10.1126/science.1140321 · Cited by 3,075 · see citing works
A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase
Savitsky, K., Bar-Shira, A., Gilad, S., Rotman, G., Ziv, Y., Vanagaite, L., Tagle, D. A., Smith, S., Uziel, T., Sfez, S., et al. (1995) · Science · doi:10.1126/science.7792600 · Cited by 2,785 · see citing works
Haberland, M., Montgomery, R. L., & Olson, E. N. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2485 · Cited by 2,541 · see citing works
Yoshida, M., Kijima, M., Akita, M., & Beppu, T. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44885-x · Cited by 1,856 · see citing works
Serine/threonine phosphatases: mechanism through structure
Shi, Y. (2009) · Cell · doi:10.1016/j.cell.2009.10.006 · Cited by 1,488 · see citing works
Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia
Barlow, C., Hirotsune, S., Paylor, R. E., Liyanage, M., Eckhaus, M., Collins, F. S., Shiloh, Y., Crawley, J. N., Ried, T., Tagle, D. A., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)80086-0 · Cited by 1,450 · see citing works
The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men
Yang, X., & Seto, E. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2346 · Cited by 1,239 · see citing works
Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation
McKinsey, T. A., Zhang, C., Lu, J., & Olson, E. N. (2000) · Nature · doi:10.1038/35040593 · Cited by 1,051 · see citing works
Xu, Y., Ashley, T., Brainerd, E. E., Bronson, R. T., Meyn, M. S., & Baltimore, D. (1996) · Genes & Development · doi:10.1101/gad.10.19.2411 · Cited by 830 · see citing works
CBP Histone Acetyltransferase Activity Is a Critical Component of Memory Consolidation
Korzus, E., Rosenfeld, M. G., & Mayford, M. (2004) · Neuron · doi:10.1016/j.neuron.2004.06.002 · Cited by 823 · see citing works
Three proteins define a class of human histone deacetylases related to yeast Hda1p
Grozinger, C. M., Hassig, C. A., & Schreiber, S. L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.9.4868 · Cited by 770 · see citing works
THE GENETIC DEFECT IN ATAXIA-TELANGIECTASIA
Lavin, M. F., & Shiloh, Y. (1997) · Annual Review of Immunology · doi:10.1146/annurev.immunol.15.1.177 · Cited by 644 · see citing works
Grozinger, C. M., & Schreiber, S. L. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.140199597 · Cited by 587 · see citing works
HDAC4 deacetylase associates with and represses the MEF2 transcription factor
Miska, E. A., Karlsson, C., Langley, E., Nielsen, S. J., Pines, J., & Kouzarides, T. (1999) · The EMBO Journal · doi:10.1093/emboj/18.18.5099 · Cited by 551 · see citing works
HDAC4, a Human Histone Deacetylase Related to Yeast HDA1, Is a Transcriptional Corepressor
Wang, A. H., Bertos, N. R., Vezmar, M., Pelletier, N., Crosato, M., Heng, H. H., Th’ng, J., Han, J., & Yang, X.-J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.11.7816 · Cited by 294 · see citing works
Regulation of Histone Deacetylase 4 by Binding of 14-3-3 Proteins
Wang, A. H., Kruhlak, M. J., Wu, J., Bertos, N., Vezmar, M., Posner, B. I., Bazett‐Jones, D. P., & Yang, X. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.18.6904-6912.2000 · Cited by 275 · see citing works
Fejes, A. P., Robertson, G., Bilenky, M., Varhol, R., Bainbridge, M., & Jones, S. J. M. (2008) · Bioinformatics · doi:10.1093/bioinformatics/btn305 · Cited by 272 · see citing works
HDAC4 Regulates Neuronal Survival in Normal and Diseased Retinas
Chen, B., & Cepko, C. L. (2009) · Science · doi:10.1126/science.1166226 · Cited by 192 · see citing works
Intracellular Trafficking of Histone Deacetylase 4 Regulates Neuronal Cell Death
Bolger, T. A., & Yao, T. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1826-05.2005 · Cited by 190 · see citing works
Backs, J., Backs, T., Bezprozvannaya, S., McKinsey, T. A., & Olson, E. N. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01611-07 · Cited by 179 · see citing works
Histone deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression
Méjat, A., Ramond, F., Bassel‐Duby, R., Khochbin, S., Olson, E. N., & Schaeffer, L. (2005) · Nature Neuroscience · doi:10.1038/nn1408 · Cited by 169 · see citing works
Calcium Regulates Transcriptional Repression of Myocyte Enhancer Factor 2 by Histone Deacetylase 4
Youn, H., Grozinger, C. M., & Liu, J. O. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000304200 · Cited by 163 · see citing works
Zhao, X., Ito, A., Kane, C. D., Liao, T.-S., Bolger, T. A., Lemrow, S. M., Means, A. R., & Yao, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105086200 · Cited by 151 · see citing works
Liu, Y., Randall, W. R., & Schneider, M. F. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200408128 · Cited by 150 · see citing works
HDAC4 inhibits cell‐cycle progression and protects neurons from cell death
Majdzadeh, N., Wang, L., Morrison, B. E., Bassel‐Duby, R., Olson, E. N., & D’Mello, S. R. (2008) · Developmental Neurobiology · doi:10.1002/dneu.20637 · Cited by 135 · see citing works
The role of the DNA damage response in neuronal development, organization and maintenance
Barzilai, A., Biton, S., & Shiloh, Y. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.03.005 · Cited by 135 · see citing works
PP2A Regulates HDAC4 Nuclear Import
Paroni, G., Cernotta, N., Dello Russo, C., Gallinari, P., Pallaoro, M., Foti, C., Talamo, F., Orsatti, L., Steinkühler, C., & Brancolini, C. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-06-0623 · Cited by 126 · see citing works
Kuljiš, R. O., Xu, Y., Aguila, M. C., & Baltimore, D. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.23.12688 · Cited by 100 · see citing works
Nervi, C., Borello, U., Fazi, F., Buffa, V., Pelicci, P. G., & Cossu, G. (2001) · PubMed · Cited by 91 · see citing works
Chan, J. K. L., Sun, L., Yang, X., Zhu, G., & Wu, Z. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301922200 · Cited by 79 · see citing works
Regional and subcellular distribution of HDAC4 in mouse brain
Darcy, M. J., Calvin, K., Cavnar, K., & Ouimet, C. C. (2010) · Journal of Comparative Neurology · doi:10.1002/cne.22241 · Cited by 69 · see citing works
Clinical and Genetic Features of Ataxia-telangiectasia
Bundey, S. (1994) · International Journal of Radiation Biology · doi:10.1080/09553009414551821 · Cited by 55 · see citing works
HISTONE DEACETYLASES AS TARGETS FOR THE TREATMENT OF HUMAN NEURODEGENERATIVE DISEASES
D'Mello, S. (2009) · Drug News and Perspectives · doi:10.1358/dnp.2009.9.1428871 · Cited by 53 · see citing works
Histone deacetylases as targets for the treatment of human neurodegenerative diseases
D’Mello, S. R. (2009) · Drug News & Perspectives · doi:10.1358/dnp.2009.22.9.1437959 · Cited by 53 · see citing works
Progressive ataxia in childhood with particular reference to ataxia‐telangiectasia
Sedgwick, R. P., & Boder, E. (1960) · Neurology · doi:10.1212/wnl.10.7.705 · Cited by 52 · see citing works
In Vivo Transduction of Cerebellar Purkinje Cells Using Adeno-Associated Virus Vectors
Kaemmerer, W. F., Reddy, R. G., Warlick, C. A., Hartung, S. D., McIvor, R. S., & Low, W. C. (2000) · Molecular Therapy · doi:10.1006/mthe.2000.0134 · Cited by 47 · see citing works
Class IIA HDACs in the regulation of neurodegeneration
Majdzadeh, N. (2007) · Frontiers in bioscience · doi:10.2741/2745 · Cited by 44 · see citing works
Cooper, J. F., & Kusnecov, A. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.07.034 · Cited by 20 · see citing works
Self-citationExpression of human ATM cDNA in Atm-deficient mouse brain mediated by HSV-1 amplicon vector
Cortés, M. L., Oehmig, A., Perry, K. F., et al. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.05.055 · Cited by 16 · see citing works
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Shiloh, Y., & Ziv, Y. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3546 · Cited by 1,649 · see citing works
Fang, E. F., Kassahun, H., Croteau, D. L., Scheibye-Knudsen, M., Marosi, K., Lu, H., Shamanna, R. A., Kalyanasundaram, S., Bollineni, R. C., Wilson, M. A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.004 · Cited by 575 · see citing works
Self-citationHDAC4 Governs a Transcriptional Program Essential for Synaptic Plasticity and Memory
Sando, R., Gounko, N., Pieraut, S., Liao, L., Yates, J., & Maximov, A. (2012) · Cell · doi:10.1016/j.cell.2012.09.037 · Cited by 274 · see citing works
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
“143,144 In contrast, the role of cytoplasmic HDACs is less understood.”
BackgroundChow, H.-M., Shi, M., Cheng, A., Gao, Y., Chen, G., Song, X., So, R. W. L., Zhang, J., & Herrup, K. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0505-1 · Cited by 171 · see citing works
Self-citationGenomic integrity and the ageing brain
Chow, H.-M., & Herrup, K. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn4020 · Cited by 174 · see citing works
Self-citationDNA damage in the oligodendrocyte lineage and its role in brain aging
Tse, K.-H., & Herrup, K. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.05.006 · Cited by 108 · see citing works
Self-citationMathias, R. A., Guise, A. J., & Cristea, I. M. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.o114.046565 · Cited by 93 · see citing works
A nervous predisposition to unrepaired DNA double strand breaks
Reynolds, J. J., & Stewart, G. S. (2013) · DNA Repair · doi:10.1016/j.dnarep.2013.04.011 · Cited by 26 · see citing works
- Authors
- Li, J., Chen, J., Ricupero, C. L., Hart, R. P., Schwartz, M. S., Kusnecov, A., & Herrup, K.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Herrup, Karl
- Venue
- Nature Medicine
- Published
- 2012-04-01
- Volume
- 18
- Issue
- 5
- Pages
- 783-790
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3378917
- OpenAlex
- W2158225056
- Cited by
- 210
- References
- 41
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 16 · 2023: 7 · 2022: 15 · 2021: 8 · 2020: 19 · 2019: 12 · 2018: 13 · 2017: 17 · 2016: 21 · 2015: 22 · 2014: 20 · 2013: 18 · 2012: 8
- FWCI
- 8.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health (1r21mh085088-01a1)
- National Institute of Mental Health (R21 MH085088., R01MH060706, MH 60706)
- National Cancer Institute (RC1CA147187)
- National Institute of Neurological Disorders and Stroke (R01NS020591, NS20591, R01NS071022, NS71022)
- National Institute of Environmental Health Sciences (P30ES05022, P30ES005022)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (N01 HD 43383, N01-HD-4-3368)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- ataxia telangiectasia, ATM deficiency, HDAC4, nuclear accumulation, neurodegeneration, cerebellar neurons, histone deacetylation, MEF2A, CREB, protein phosphatase 2A, cytoplasmic localization, neuronal gene expression, motor impairment
- MeSH terms
- Animals, Ataxia Telangiectasia, Cell Nucleus, DNA-Binding Proteins, Female, Histone Deacetylases, Histones, Hydroxamic Acids, Male, Phosphorylation, Protein Serine-Threonine Kinases, Cyclic AMP Response Element-Binding Protein, Myogenic Regulatory Factors, Cell Cycle Proteins, Neurodegenerative Diseases, Active Transport, Cell Nucleus, Tumor Suppressor Proteins, Mice, Protein Phosphatase 2, Ataxia Telangiectasia Mutated Proteins, MEF2 Transcription Factors
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