TDP-43 suppresses tau expression via promoting its mRNA instability

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 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.

TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

“…These results may indicate an early stage of Tau aggregation associated with TDP-43 expression increasing cytoplasmic phosphorylated TDP-43 accumulation. Which supports the role TDP-43 plays in Tau mRNA metabolism described by Gu and colleagues (Gu et al, 2017). …”

“…Recently, a study described an interaction between TDP-43 and Tau mRNA 3′UTR. When TDP-43 interacts with Tau mRNA expression of Tau is suppressed (Gu et al, 2017). When pathological TDP-43 accumulates in the cytoplasm in this TDP-43 M337V ALS mouse model, Tau expression increases and aggregates (Gu et al, 2017).…”

“…When TDP-43 interacts with Tau mRNA expression of Tau is suppressed (Gu et al, 2017). When pathological TDP-43 accumulates in the cytoplasm in this TDP-43 M337V ALS mouse model, Tau expression increases and aggregates (Gu et al, 2017). We next examined mouse Tau mRNA isoforms (NM_001038609 isoform A and NM_001285455 isoform D) and human APP mRNA and found that both were not increased due to changes in TDP-43 expression (Supplementary Fig.…”

“…This diffuse staining of thioflavin S may indicate an early stage of aggregation or pre-tangle formation not normally seen in APP/PS1 mice. As with the ALS model described above, when phosphorylated TDP-43 accumulates in the cytoplasm, Tau mRNA becomes more stable and expression is increased (Gu et al, 2017). Though we show no increase in total Tau or phosphorylated Tau (PHF1 or pTauSer396), we do show aggregation, which suggests a role for TDP-43 in Tau aggregation.…”

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

“…It remains to be determined if susceptibility to, or DNA damage itself, may be involved in AD pathogenesis. Additionally, a dichotomous relationship was recently observed between TDP-43 and tau levels during Alzheimer’s pathogenesis, with TDP-43 being shown to regulate tau protein expression by destabilizing its cognate mRNA [85]. …”