Abstract
Stroke is a leading global cause of mortality and disability. Less than 5% of patients are able to receive tissue plasminogen activator thrombolysis within the necessary timeframe. Focusing on the process of neuronal apoptosis in the penumbra, which lasts from hours to days after ischaemia, appears to be promising. Here we report that tumour necrosis factor receptor-associated factor 1 (TRAF1) expression is markedly induced in wild-type mice 6 h after stroke onset. Using genetic approaches, we demonstrate that increased neuronal TRAF1 leads to elevated neuronal death and enlarged ischaemic lesions, whereas TRAF1 deficiency is neuroprotective. In addition, TRAF1-mediated neuroapoptosis correlates with the activation of the JNK pro-death pathway and inhibition of the Akt cell survival pathway. Finally, TRAF1 is found to exert pro-apoptotic effects via direct interaction with ASK1. Thus, ASK1 positively and negatively regulates the JNK and Akt signalling pathways, respectively. Targeting the TRAF1/ASK1 pathway may provide feasible therapies for stroke long after onset.
| Original language | English (US) |
|---|---|
| Article number | 2852 |
| Journal | Nature communications |
| Volume | 4 |
| DOIs | |
| State | Published - Nov 28 2013 |
Bibliographical note
Funding Information:The authors thank Professor Hidenori Ichijo, who provided the kind gift of dominant-negative ASK1 cDNA. This work was supported by grants from the National Natural Science Foundation of China (no. 81100230, no. 81330005 and no. 81070089), National Science and Technology Support Project (no. 2013YQ030923-05, no. 2011BAI15B02 and no. 2012BAI39B05), and the National Basic Research Program of China (no. 2011CB503902).
