Title: Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6
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 #
Issue Date: Jan-2010
Publisher: Nature Publishing Group
Series Title: EMBO Journal vol:29 pages:209-211
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.
ISSN: 0261-4189
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group for Neurobiology and Gene Therapy
× corresponding author
# (joint) last author

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