Inhibition of the MEK/ERK pathway suppresses immune overactivation and mitigates TDP-43 toxicity in a Drosophila model of ALS

Abstract

TDP-43 is an important DNA/RNA-binding protein that is associated with age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, its pathomechanism is not fully understood. In a transgenic RNAi screen using Drosophila as a model, we uncovered that knockdown (KD) of Dsor1 (the Drosophila MAPK kinase dMEK) suppressed TDP-43 toxicity without altering TDP-43 phosphorylation or protein levels. Further investigation revealed that the Dsor1 downstream gene rl (dERK) was abnormally upregulated in TDP-43 flies, and neuronal overexpression of dERK induced profound upregulation of antimicrobial peptides (AMPs). We also detected a robust immune overactivation in TDP-43 flies, which could be suppressed by downregulation of the MEK/ERK pathway in TDP-43 fly neurons. Furthermore, neuronal KD of abnormally increased AMPs improved the motor function of TDP-43 flies. On the other hand, neuronal KD of Dnr1, a negative regulator of the Drosophila immune deficiency (IMD) pathway, activated the innate immunity and boosted AMP expression independent of the regulation by the MEK/ERK pathway, which diminished the mitigating effect of RNAi-dMEK on TDP-43 toxicity. Finally, we showed that an FDA-approved MEK inhibitor trametinib markedly suppressed immune overactivation, alleviated motor deficits and prolonged the lifespan of TDP-43 flies, but did not exhibit a lifespan-extending effect in Alzheimer disease (AD) or spinocerebellar ataxia type 3 (SCA3) fly models. Together, our findings suggest an important role of abnormal elevation of the MEK/ERK signaling and innate immunity in TDP-43 pathogenesis and propose trametinib as a potential therapeutic agent for ALS and other TDP-43-related diseases.

An unscheduled switch to endocycles induces a reversible senescent arrest that impairs growth of theDrosophilawing disc

“…We also performed the opposite experiment and increased JNK signaling in iECs by overexpressing hemipterous ( hep ), the upstream kinase that phosphorylates and activates JNK. 78,79 Expression of UAS-hep restricted iEC growth and resulted in smaller and less polyploid iECs (Fig. 6L-N).…”

Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924

“…Sulpiride is a neuroleptic and all hit compounds of a previous large-scale chemical screen in TDP-43 A315T worms and TDP-43 G348C zebrafish were neuroleptics. 111 Additionally, while there is evidence of increased MAP kinase signaling in ALS patients as well as in animal and iPSC models, 57,[112][113][114][115] two compounds identified here were MAP kinase inhibitors (XMD-892, XMD-885). Finally, XMD-892 116 and other compounds (tacedinaline, [117][118][119] MLN4924, 120 piperlongumine, 121,122 prunetin 123 ) have also been under investigation for their antioxidant, anti-inflammatory, anti-ischemic, neuroprotective, and/or antitumour properties.…”