TDP-43 suppresses tau expression via promoting its mRNA instability

• Jianlan Gu ^[1] ; Feng Wu ^[1] ; Wen Xu ^[1] ; Jianhua Shi ^[1] ; Wen Hu ^[1] ; Nana Jin ^[1] ; Wei Qian ^[1] ; Xinglong Wang ^[2] ; Khalid Iqbal ^[3] ; Cheng-Xin Gong ^[1] ; Fei Liu ^[1]
  1. [1] Nantong University

     Nantong University

     China

     
  2. [2] Case Western Reserve University

     Case Western Reserve University

     City of Cleveland, Estados Unidos

     
  3. [3] Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA

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• Localización: Nucleic acids research, ISSN 0305-1048, Vol. 45, Nº. 10, 2017, págs. 6177-6193
• Idioma: inglés
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• Resumen

  • 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 tau mRNA 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.