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, Anderson L. Marlene, 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

Research output: Contribution to journalArticle

163 Scopus citations

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, HDAC6dependent 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.

Original languageEnglish (US)
Pages (from-to)209-221
Number of pages13
JournalEMBO Journal
Volume29
Issue number1
DOIs
StatePublished - Jan 6 2010

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Keywords

  • Frontotemporal dementia
  • HDAC6
  • Microarray
  • Motoneuron disease
  • TDP-43

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Fiesel, F. C., Voigt, A., Weber, S. S., Van Den Haute, C., Waldenmaier, A., Görner, K., Walter, M., Marlene, A. L., Kern, J. V., Rasse, T. M., Schmidt, T., Springer, W., Kirchner, R., Bonin, M., Neumann, M., Baekelandt, V., Alunni-Fabbroni, M., Schulz, J. B., & Kahle, P. J. (2010). Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6. EMBO Journal, 29(1), 209-221. https://doi.org/10.1038/emboj.2009.324