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

Molecular Neurodegeneration

Anthony R White⁴  Peter J Crouch⁴  Katja M Kanninen⁴  Marie A Bogoyevitch³  Masato Hasegawa⁵  Takashi Nonaka⁵  Colin L Masters²  Qiao-Xin Li²  Aphrodite Caragounis⁴  Jeffrey R Liddell⁴  Katherine A Price⁴  Dominic CH Ng³  Laura J Vella¹  Sarah J Parker⁴  Jodi Meyerowitz⁴ 

[1] Ludwig Institute for Cancer Research, Austin Hospital, Harold Stokes Building, 145-163 Studley Road, Heidelberg, Victoria, 3084, Australia;The Mental Health Research Institute, Parkville, Victoria, 3052, Australia;Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, 3052, Australia;Department of Pathology, The University of Melbourne, Victoria, 3010, Australia;Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo 156-8585, Japan

关键词: hnRNP;    paraquat;    oxidative stress;    kinases;    JNK;    stress granules;    TDP-43;   

Others  :  865704
DOI  :  10.1186/1750-1326-6-57

 received in 2011-04-15, accepted in 2011-08-08,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Meyerowitz et al; licensee BioMed Central Ltd.

【 图 表 】

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