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Knockdown of transactive response DNA‐binding protein (TDP‐43) downregulates histone deacetylase 6

Fabienne C Fiesel, Aaron Voigt, Stephanie S Weber, Chris Van den Haute, Andrea Waldenmaier, Karin Görner, Michael Walter, Marlene L Anderson, Jeannine V Kern, Tobias M Rasse, Thorsten Schmidt, Wolfdieter Springer, Roland Kirchner, Michael Bonin, Manuela Neumann, Veerle Baekelandt, Marianna Alunni‐Fabbroni, Jörg B Schulz, Philipp J Kahle

Author Affiliations

  1. Fabienne C Fiesel*,1,
  2. Aaron Voigt2,
  3. Stephanie S Weber1,
  4. Chris Van den Haute3,
  5. Andrea Waldenmaier4,
  6. Karin Görner4,
  7. Michael Walter5,
  8. Marlene L Anderson1,
  9. Jeannine V Kern6,
  10. Tobias M Rasse6,
  11. Thorsten Schmidt7,
  12. Wolfdieter Springer1,
  13. Roland Kirchner4,
  14. Michael Bonin5,
  15. Manuela Neumann8,
  16. Veerle Baekelandt3,
  17. Marianna Alunni‐Fabbroni4,
  18. Jörg B Schulz2 and
  19. Philipp J Kahle*,1
  1. 1 Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Tübingen, Germany
  2. 2 Department of Neurology, University Medical Centre, RWTH Aachen, Aachen, Germany
  3. 3 Laboratory for Neurobiology and Gene Therapy, Division of Molecular Medicine, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
  4. 4 Beckman Coulter Biomedical GmbH, Munich, Germany
  5. 5 The Microarray Facility, University of Tübingen, Tübingen, Germany
  6. 6 Synaptic Plasticity Group, Hertie Institute for Clinical Brain Research, Tübingen, Germany
  7. 7 Department of Medical Genetics, University of Tübingen, Tübingen, Germany
  8. 8 Institute of Neuropathology, University of Zurich, Zurich, Switzerland
  1. *Corresponding authors. Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University Clinics Tübingen, Otfried‐Müller‐Strasse 27, 72076 Tübingen, Germany. Tel.: +49 7071 29 81968; Fax: +49 7071 29 4620; E-mail: fabienne.fiesel{at}klinikum.uni-tuebingen.de or Tel.: +49 7071 29 81970; Fax: +49 7071 29 4620; E-mail: Philipp.Kahle{at}Uni-Tuebingen.de
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Abstract

TDP‐43 is an RNA/DNA‐binding protein implicated in transcriptional repression and mRNA processing. Inclusions of TDP‐43 are hallmarks of frontotemporal dementia and amyotrophic lateral sclerosis. Besides aggregation of TDP‐43, loss of nuclear localization is observed in disease. To identify relevant targets of TDP‐43, we performed expression profiling. Thereby, histone deacetylase 6 (HDAC6) downregulation was discovered on TDP‐43 silencing and confirmed at the mRNA and protein level in human embryonic kidney HEK293E and neuronal SH‐SY5Y cells. This was accompanied by accumulation of the major HDAC6 substrate, acetyl‐tubulin. HDAC6 levels were restored by re‐expression of TDP‐43, dependent on RNA binding and the C‐terminal protein interaction domains. Moreover, TDP‐43 bound specifically to HDAC6 mRNA arguing for a direct functional interaction. Importantly, in vivo validation in TDP‐43 knockout Drosophila melanogaster confirmed the specific downregulation of HDAC6. HDAC6 is necessary for protein aggregate formation and degradation. Indeed, HDAC6‐dependent reduction of cellular aggregate formation and increased cytotoxicity of polyQ‐expanded ataxin‐3 were found in TDP‐43 silenced cells. In conclusion, loss of functional TDP‐43 causes HDAC6 downregulation and might thereby contribute to pathogenesis.

  • Received May 28, 2009.
  • Accepted October 12, 2009.
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