C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress

• Main Authors: Masters Colin L, Li Qiao-Xin, Caragounis Aphrodite, Liddell Jeffrey R, Price Katherine A, Ng Dominic CH, Vella Laura J, Parker Sarah J, Meyerowitz Jodi, Nonaka Takashi, Hasegawa Masato, Bogoyevitch Marie A, Kanninen Katja M, Crouch Peter J, White Anthony R
• Format: Article
• Language: English
• Published: BMC 2011-08-01
• Series: Molecular Neurodegeneration
• Subjects: TDP-43; stress granules; JNK; kinases; oxidative stress; paraquat; hnRNP
• Online Access: http://www.molecularneurodegeneration.com/content/6/1/57

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p>