期刊
MOLECULAR NEURODEGENERATION
卷 6, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/1750-1326-6-57
关键词
TDP-43; stress granules; JNK; kinases; oxidative stress; paraquat; hnRNP
资金
- National Health and Medical Research Council of Australia
- Australian Research Council of Australia (ARC)
- Faculty of Medicine, Dentistry and Health Sciences
- Melbourne Neuroscience Institute
- Motor Neuron Disease Research Institute of Australia
- CASS foundation
- NHMRC
- University of Melbourne
- Sigrid Juselius Foundation, Finland
- Mental Health Research Institute
- Tokyo Institute of Psychiatry
- Grants-in-Aid for Scientific Research [23240050] Funding Source: KAKEN
Background: TDP-43 proteinopathies are characterized by loss of nuclear TDP-43 expression and formation of C-terminal TDP-43 fragmentation and accumulation in the cytoplasm. Recent studies have shown that TDP-43 can accumulate in RNA stress granules (SGs) in response to cell stresses and this could be associated with subsequent formation of TDP-43 ubiquinated protein aggregates. However, the initial mechanisms controlling endogenous TDP-43 accumulation in SGs during chronic disease are not understood. In this study we investigated the mechanism of TDP-43 processing and accumulation in SGs in SH-SY5Y neuronal-like cells exposed to chronic oxidative stress. Cell cultures were treated overnight with the mitochondrial inhibitor paraquat and examined for TDP-43 and SG processing. Results: We found that mild stress induced by paraquat led to formation of TDP-43 and HuR-positive SGs, a proportion of which were ubiquitinated. The co-localization of TDP-43 with SGs could be fully prevented by inhibition of c-Jun N-terminal kinase (JNK). JNK inhibition did not prevent formation of HuR-positive SGs and did not prevent diffuse TDP-43 accumulation in the cytosol. In contrast, ERK or p38 inhibition prevented formation of both TDP-43 and HuR-positive SGs. JNK inhibition also inhibited TDP-43 SG localization in cells acutely treated with sodium arsenite and reduced the number of aggregates per cell in cultures transfected with C-terminal TDP-43 162-414 and 219-414 constructs. Conclusions: Our studies are the first to demonstrate a critical role for kinase control of TDP-43 accumulation in SGs and may have important implications for development of treatments for FTD and ALS, targeting cell signal pathway control of TDP-43 aggregation.
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