Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-27485
Fiesel, F C; Voigt, A; Weber, S S; Van den Haute, C; Waldenmaier, A; Görner, K; Walter, M; Anderson, M L; Kern, J V; Rasse, T M; Schmidt, T; Springer, W; Kirchner, R; Bonin, M; Neumann, M; Baekelandt, V; Alunni-Fabbroni, M; Schulz, J B; Kahle, P J (2010). Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6. The EMBO Journal, 29(1):209-221.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology|
|DDC:||570 Life sciences; biology
610 Medicine & health
|Deposited On:||20 Mar 2010 15:07|
|Last Modified:||28 Nov 2013 02:13|
|Publisher:||Nature Publishing Group|
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