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Knockdown of transactive response DNA‐binding protein (TDP‐43) downregulates histone deacetylase 6
Author(s) -
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,
AlunniFabbroni Marianna,
Schulz Jörg B,
Kahle Philipp J
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.324
Subject(s) - biology , gene knockdown , histone deacetylase , histone , histone deacetylase 2 , hdac4 , genetics , dna binding protein , dna damage , dna , microbiology and biotechnology , cancer research , computational biology , gene , transcription factor
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.