PMID- 37340309
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230701
IS  - 1742-4933 (Print)
IS  - 1742-4933 (Electronic)
IS  - 1742-4933 (Linking)
VI  - 20
IP  - 1
DP  - 2023 Jun 20
TI  - Inhibition of the MEK/ERK pathway suppresses immune overactivation and mitigates 
      TDP-43 toxicity in a Drosophila model of ALS.
PG  - 27
LID - 10.1186/s12979-023-00354-8 [doi]
LID - 27
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Yue, Wenkai
AU  - Yue W
AD  - Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China.
FAU - Deng, Xue
AU  - Deng X
AD  - Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China.
FAU - Wang, Zhao
AU  - Wang Z
AD  - Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
FAU - Jiang, Mingsheng
AU  - Jiang M
AD  - Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China.
FAU - Hu, Rirong
AU  - Hu R
AD  - Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China.
FAU - Duan, Yongjia
AU  - Duan Y
AD  - Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China.
FAU - Wang, Qiangqiang
AU  - Wang Q
AD  - Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
FAU - Cui, Jihong
AU  - Cui J
AD  - Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
FAU - Fang, Yanshan
AU  - Fang Y
AD  - Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China. 
      fangys@sioc.ac.cn.
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China. 
      fangys@sioc.ac.cn.
LA  - eng
GR  - 31970697/National Natural Science Foundation of China/
GR  - 201409003300/Science and Technology Commission of Shanghai Municipality/
PT  - Journal Article
DEP - 20230620
PL  - England
TA  - Immun Ageing
JT  - Immunity & ageing : I & A
JID - 101235427
PMC - PMC10280928
OTO - NOTNLM
OT  - ALS
OT  - ERK
OT  - Innate immunity
OT  - MAPK signaling
OT  - MEK
OT  - TDP-43
COIS- The authors declare no competing interests.
EDAT- 2023/06/21 01:07
MHDA- 2023/06/21 01:08
PMCR- 2023/06/20
CRDT- 2023/06/20 23:34
PHST- 2022/12/18 00:00 [received]
PHST- 2023/06/08 00:00 [accepted]
PHST- 2023/06/21 01:08 [medline]
PHST- 2023/06/21 01:07 [pubmed]
PHST- 2023/06/20 23:34 [entrez]
PHST- 2023/06/20 00:00 [pmc-release]
AID - 10.1186/s12979-023-00354-8 [pii]
AID - 354 [pii]
AID - 10.1186/s12979-023-00354-8 [doi]
PST - epublish
SO  - Immun Ageing. 2023 Jun 20;20(1):27. doi: 10.1186/s12979-023-00354-8.