TDP-43 suppresses tau expression via promoting its mRNA instability

Jianlan Gu, Feng Wu, Wen Xu, Jianhua Shi, Wen Hu, Nana Jin, Wei Qian, Xinglong Wang, Khalid Iqbal, Cheng Xin Gong, Fei Liu

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

In the brains of individuals with Alzheimer's disease (AD) and chronic traumatic encephalopathy, tau pathology is accompanied usually by intracellular aggregation of transactive response DNA-binding protein 43 (TDP-43). However, the role of TDP-43 in tau pathogenesis is not understood. Here, we investigated the role of TDP-43 in tau expression in vitro and in vivo. We found that TDP-43 suppressed tau expression by promoting its mRNA instability through the UG repeats of its 3'-untranslated region (3'-UTR). The C-terminal region of TDP-43 was required for this function. Neurodegenerative diseases-causing TDP- 43 mutations affected tau mRNA instability differentially, in that some promoted and others did not significantly affect taumRNA instability. The expression levels of tau and TDP-43 were inverse in the frontal cortex and the cerebellum. Accompanied with cytoplasmic accumulation of TDP-43, tau expression was elevated in TDP-43M337V transgenic mouse brains. The level of TDP-43, which is decreased in AD brains, was found to correlate negatively with the tau level in human brain. Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. Down-regulation of TDP-43 may be involved in the tau pathology in AD and related neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)6177-6193
Number of pages17
JournalNucleic acids research
Volume45
Issue number10
DOIs
StatePublished - Jun 2 2017
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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