Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6
Fiesel, Fabienne C × Voigt, Aaron Weber, Stephanie S Van Den Haute, Chris Waldenmaier, Andrea Görner, Karin Walter, Michael Anderson, Marlene L Kern, Jeannine V Rasse, Tobias M Schmidt, Thorsten Springer, Wolfdieter Kirchner, Roland Bonin, Michael Neumann, Manuela Baekelandt, Veerle Alunni-Fabbroni, Marianna Schulz, Jörg B Kahle, Philipp J #
Nature Publishing Group
EMBO Journal vol:29 pages:209-211
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.