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| Status |
Public on Oct 20, 2009 |
| Title |
Knockdown of transactive response DNA-binding protein TDP-43 downregulates histone deacetylase 6 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
TDP-43 is an RNA/DNA-binding protein implicated in transcriptional repression and mRNA processing. Inclusions of TDP-43 are hallmarks of frontotemporal dementias 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 an expression profiling study. Thereby, histone deacetylase 6 (HDAC6) downregulation was discovered upon TDP-43 silencing on 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. Expression of wild-type but neither RNA-binding- nor nuclear-localization-deficient TDP-43 restored HDAC6 expression. Moreover, TDP-43 bound specifically to HDAC6 mRNA arguing for a direct functional interaction. Importantly, in vivo validation in TDP-43 knockout Drosophila melanogaster also showed HDAC6 mRNA decrease. HDAC6 is necessary for protein aggregate formation and degradation. Indeed, downregulation of HDAC6 reduced aggregate formation and increased cytotoxicity of expanded poly-glutamine ataxin-3 in TDP-43 silenced cells. This was completely restored by co-transfection with HDAC6. In conclusion, loss of functional TDP-43 causes HDAC6 downregulation and might thereby contribute to pathogenesis.
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| Overall design |
Comparison of TDP-43 knockdown in HEK293E cells against cells transfected with scrambled siRNA. 4 independend transfections per siRNA were used.
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| Contributor(s) |
Fiesel FC, Anderson ML, Van den Haute C, Voigt A, Walter M, Schmidt T, Neumann M, Klein S, Springer W, Schulz JB, Bonin M, Baekelandt V, Kahle PJ |
| Citation(s) |
19910924 |
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| Submission date |
Oct 19, 2009 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Michael H. Walter |
| E-mail(s) |
[email protected]
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| Organization name |
University of Tuebingen
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| Department |
Department of Medical Genetics
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| Lab |
The Microarray Facility Tübingen
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| Street address |
Calwer Str. 7
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| City |
Tuebingen |
| ZIP/Postal code |
72076 |
| Country |
Germany |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (8)
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| GSM463015 |
HEK293E cells, scrambled siRNA, replicate 1 |
| GSM463016 |
HEK293E cells, scrambled siRNA, replicate 2 |
| GSM463017 |
HEK293E cells, scrambled siRNA, replicate 3 |
| GSM463018 |
HEK293E cells, scrambled siRNA, replicate 4 |
| GSM463019 |
HEK293E cells, TDP-43 siRNA, replicate 1 |
| GSM463020 |
HEK293E cells, TDP-43 siRNA, replicate 2 |
| GSM463021 |
HEK293E cells, TDP-43 siRNA, replicate 3 |
| GSM463022 |
HEK293E cells, TDP-43 siRNA, replicate 4 |
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| Relations |
| BioProject |
PRJNA121403 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE18632_RAW.tar |
40.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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