| http://purl.uniprot.org/citations/37340309 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/37340309 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.org/dc/terms/identifier | "doi:10.1186/s12979-023-00354-8"xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/author | "Fang Y."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/author | "Deng X."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/author | "Wang Q."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/author | "Wang Z."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/author | "Cui J."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/author | "Duan Y."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/author | "Hu R."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/author | "Yue W."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/author | "Jiang M."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/date | "2023"xsd:gYear |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/name | "Immun Ageing"xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/pages | "27"xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/title | "Inhibition of the MEK/ERK pathway suppresses immune overactivation and mitigates TDP-43 toxicity in a Drosophila model of ALS."xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://purl.uniprot.org/core/volume | "20"xsd:string |
| http://purl.uniprot.org/citations/37340309 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/37340309 |
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