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

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.

Pubmed ID: 19910924

Authors

  • Fiesel FC
  • Voigt A
  • Weber SS
  • Van den Haute C
  • Waldenmaier A
  • Görner K
  • Walter M
  • Anderson ML
  • Kern JV
  • Rasse TM
  • Schmidt T
  • Springer W
  • Kirchner R
  • Bonin M
  • Neumann M
  • Baekelandt V
  • Alunni-Fabbroni M
  • Schulz JB
  • Kahle PJ

Journal

The EMBO journal

Publication Data

January 6, 2010

Associated Grants

None

Mesh Terms

  • Animals
  • Base Sequence
  • Cell Line
  • Cell Nucleus
  • DNA-Binding Proteins
  • Down-Regulation
  • Drosophila Proteins
  • Drosophila melanogaster
  • Histone Deacetylases
  • Humans
  • Neurons
  • RNA Interference
  • RNA, Messenger
  • RNA, Small Interfering
  • Recombinant Proteins
  • TDP-43 Proteinopathies