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Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia

Abstract

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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Figure 1: Nuclear accumulation of HDAC4 in ATM-deficient neurons leads to the suppression of MEF2- and CREB-related transcriptional activities.
Figure 2: Nuclear accumulation of HDAC4 leads to global effects on histone acetylation and neuronal gene expression.
Figure 3: Inhibition of HDAC4 and blocking the nuclear accumulation of HDAC4 partially reverses the ataxia telangiectasia phenotype.
Figure 4: HDAC4 cytoplasmic localization requires phosphorylation of HDAC4 and is independent of DNA damage.
Figure 5: The PP2A-A subunit, PR65, is a ATM target and mediates nuclear accumulation of HDAC4 in ATM-deficient neurons.
Figure 6: Blocking nuclear HDAC4 activity rescues the Atm−/− phenotype in vivo and in vitro.

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Acknowledgements

We thank Y. Xu (University of California San Diego) for providing homozygous mice carrying the Atm knockout mutation, tm1Bal. We thank R. Gatti (University of California Los Angeles) for sharing human ataxia telangiectasia paraffin-fixed samples. Human frozen tissue was obtained from the National Institute of Child Health and Human Development (NICHD) Brain and Tissue Bank for Developmental Disorders (NICHD contracts N01-HD-4-3368 and N01-HD-4-3383). We thank M.B. Kastan (Duke University), T. Yao (Duke University) and S. Schreiber (Harvard University) for providing the wild-type and kinase-dead Flag-ATM, GFP-HDAC4 and Flag-HADC4 plasmids. M. Swerdel prepared the SOLiD ChIP-seq libraries. The long-term support of the Ataxia Telangiectasia Children's Project to K.H. is gratefully acknowledged. This work was also supported by grants from the US National Institutes of Health (NS20591 and NS71022) to K.H., R.P.H. (R21 MH085088) and A.K. (MH60706 and NIEHS P30ES05022). C.L.R. is a National Science Foundation Integrative Graduate Education and Research Traineeship fellow.

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J.L. and K.H. designed the experiments, analyzed data and wrote the manuscript. C.L.R. and R.P.H. developed, carried out and analyzed data for the ChIP-seq analyses. J.L. and J.C. carried out the immunocytochemistry experiments. J.C. performed all of the qPCR experiments. J.L. and A.K. carried out the mouse cerebellar lentiviral injections. M.S.S., J.L. and A.K. carried out behavioral tests.

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Correspondence to Karl Herrup.

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Li, J., Chen, J., Ricupero, C. et al. Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia. Nat Med 18, 783–790 (2012). https://doi.org/10.1038/nm.2709

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