title: Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6.
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.
authors.affiliation: Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Tübingen, Germany. fabienne.fiesel@klinikum.uni-tuebingen.de
authors.forename: Fabienne C
authors.initials: FC
authors.lastname: Fiesel
authors.forename: Aaron
authors.initials: A
authors.lastname: Voigt
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Weber
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.forename: Andrea
authors.initials: A
authors.lastname: Waldenmaier
authors.forename: Karin
authors.initials: K
authors.lastname: Görner
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: Marlene L
authors.initials: ML
authors.lastname: Anderson
authors.forename: Jeannine V
authors.initials: JV
authors.lastname: Kern
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Rasse
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.forename: Wolfdieter
authors.initials: W
authors.lastname: Springer
authors.forename: Roland
authors.initials: R
authors.lastname: Kirchner
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.forename: Marianna
authors.initials: M
authors.lastname: Alunni-Fabbroni
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C425683:HDAC6 protein, Drosophila; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases