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

• Published in: The EMBO journal Vol. 29; no. 1; pp. 209 - 221
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 06.01.2010; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Amyotrophic lateral sclerosis; Animals; Base Sequence; Binding sites; Cell Line; Cell Nucleus - metabolism; Cytotoxicity; Dementia disorders; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Drosophila melanogaster; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; EMBO24; frontotemporal dementia; HDAC6; Histone Deacetylase 6; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Kidneys; microarray; Molecular biology; motoneuron disease; Neurons - metabolism; Proteins; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA Interference; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; TDP-43; TDP-43 Proteinopathies - genetics; TDP-43 Proteinopathies - metabolism; frontotemporal dementia; microarray; TDP‐43; HDAC6; motoneuron disease
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2009.324

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.