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HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage

Nature Neuroscience volume 13, pages 180–189 (2010)Cite this article

Abstract

Histone deacetylase 1 (HDAC1) is a nuclear enzyme involved in transcriptional repression. We detected cytosolic HDAC1 in damaged axons in brains of humans with multiple sclerosis and of mice with cuprizone-induced demyelination, in ex vivo models of demyelination and in cultured neurons exposed to glutamate and tumor necrosis factor-α. Nuclear export of HDAC1 was mediated by the interaction with the nuclear receptor CRM-1 and led to impaired mitochondrial transport. The formation of complexes between exported HDAC1 and members of the kinesin family of motor proteins hindered the interaction with cargo molecules, thereby inhibiting mitochondrial movement and inducing localized beading. This effect was prevented by inhibiting HDAC1 nuclear export with leptomycin B, treating neurons with pharmacological inhibitors of HDAC activity or silencing HDAC1 but not other HDAC isoforms. Together these data identify nuclear export of HDAC1 as a critical event for impaired mitochondrial transport in damaged neurons.

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Figure 1: Cytosolic HDAC1 is detected in animal models of demyelination, in the brains of humans with multiple sclerosis and in demyelinated slice cultures.
Figure 2: Glutamate and TNF-α treatment of primary neuronal cultures induces neuritic beading followed by transections.
Figure 3: Cytosolic localization of HDAC1 precedes the onset of localized beading and impaired mitochondrial transport.
Figure 4: Calcium depletion prevents HDAC1 nuclear export and the onset of neuritic beading induced by treatment with glutamate and TNF-α.
Figure 5: Silencing HDAC1, but not other isoforms, prevents neurite beading.
Figure 6: CRM1-dependent nuclear export of HDAC1 is essential for the induction of damage by glutamate and TNF-α.
Figure 7: HDAC1 binding partners in demyelinated regions of cuprizone-treated mice.
Figure 8: Activity-dependent interaction of HDAC1 with motor proteins impairs mitochondrial transport.

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Acknowledgements

We thank the University of California Los Angeles Brain Bank and the UK MS Tissue Bank at Imperial College of London for providing the multiple sclerosis tissue samples, C. Seiser (University of Vienna) for providing the antibodies to the N-terminal domain of HDAC1, R. Bansal (University of Connecticut Health Science Center at Farmington) for anti-O4 hybridoma supernatant, X. Pedre and J. Li for rodent handling, S. Schreiber (Broad Institute, Massachusetts Institute of Technology) for tubacin, E. Nestler and H. Covington (Mount Sinai School of Medicine) for MS-275, S. Lagger for sharing unpublished results and critical comments on the manuscript, P. Lobel for discussions regarding MALDI-TOF data, J. Zheng and K. Teng for helpful discussion and R. Rosa for the support of the New Jersey Multiple Sclerosis Research Foundation. The study was supported by NIH-RO1 NS-42925 (P.C.) and NMSS RG-3957. J.Y.K.'s salary was supported in part also by grant no. 07-3203-BIR-E-0 from the New Jersey Commission on Traumatic Brain injury and CB1-0704-2 from the Christopher and Dana Reeve Foundation to P.C.

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  1. Graduate Program in Neuroscience at the Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey, USA

    Jin Young Kim, Siming Shen & Patrizia Casaccia

  2. Department of Neuroscience and Genetics & Genomics, Mount Sinai School of Medicine, New York, New York, USA

    Jin Young Kim, Karen Dietz, Ye He & Patrizia Casaccia

  3. Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health Imperial College Faculty of Medicine, Charing Cross Hospital Campus, London, UK

    Owain Howell & Richard Reynolds

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Contributions

The majority of the experiments in the manuscript were conducted by J.Y.K. S.S. performed the first experiments in the demyelinated mice and the first mass spectrometry. K.D. performed the in vivo confocal analysis in demyelinated mouse brains and the SAPK experiments; O.H. and R.R. performed the analysis of the human material; Y.H. performed the qt-PCR experiments. P.C. designed the experimental plan, supervised the project and wrote the manuscript.

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Correspondence to Patrizia Casaccia.

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Kim, J., Shen, S., Dietz, K. et al. HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage. Nat Neurosci 13, 180–189 (2010). https://doi.org/10.1038/nn.2471

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