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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.

SUBMITTER: Fiesel FC

PROVIDER: S-EPMC2808372 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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

Fiesel Fabienne C FC Voigt Aaron A Weber Stephanie S SS Van den Haute Chris C Waldenmaier Andrea A Görner Karin K Walter Michael M Anderson Marlene L ML Kern Jeannine V JV Rasse Tobias M TM Schmidt Thorsten T Springer Wolfdieter W Kirchner Roland R Bonin Michael M Neumann Manuela M Baekelandt Veerle V Alunni-Fabbroni Marianna M Schulz Jörg B JB Kahle Philipp J PJ

The EMBO journal 20091112 1

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 emb ...[more]

PMID: 19910924

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Project description:Importance:Transactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) ?4 allele is strongly associated with ?-amyloid (A?) aggregation and risk of AD, but its association with TDP-43 is unknown. Objective:To determine whether the APOE ?4 allele is a risk factor for TDP-43. Design, Setting, Participants:This cross-sectional, genetic-histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), A? status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage???V). We fit structural equation models to map the association between APOE and TDP-43, A?, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed A?, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants. Main Outcomes and Measures:Transactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE ?4 allele would be significantly directly and indirectly associated with TDP-43. Results:The 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE ?4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, A?, and tau, APOE ?4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P?=?.01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n?=?604 [81.8%]; estimate [SE], 0.51 [0.11]; P?<?.001), with a similar trend for those with a low likelihood of having AD (B1; n?=?134 [18.2%]; estimate [SE], 0.54 [0.32]; P?=?.10). We also found an indirect association of APOE ?4 with TDP-43 via A? and tau (estimate [SE], 0.34 [0.06]; P?<?.001), which was similar in magnitude to the direct association and an indirect association of APOE ?4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P?=?.01). Conclusions and Relevance:The study's findings, which mapped a system of risk factors and outcomes, showed that the APOE ?4 allele appears to be a risk factor for TDP-43 independently of A? in patients with AD.

Dataset Information

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

Publications

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

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