Research article
C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress
- † Equal contributors
1 Department of Pathology, The University of Melbourne, Victoria, 3010, Australia
2 Ludwig Institute for Cancer Research, Austin Hospital, Harold Stokes Building, 145-163 Studley Road, Heidelberg, Victoria, 3084, Australia
3 Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3052, Australia
4 Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, 3052, Australia
5 The Mental Health Research Institute, Parkville, Victoria, 3052, Australia
6 Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo 156-8585, Japan
Molecular Neurodegeneration 2011, 6:57 doi:10.1186/1750-1326-6-57
Published: 8 August 2011Abstract
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.
