Tat-aldose reductase prevents dopaminergic neuronal cell death by inhibiting oxidative stress and MAPK activation

Aldose reductase (AR) is known to detoxify aldehydes and prevent oxidative stress. Although AR exerts antioxidant effects, the role of AR in Parkinson's disease (Pd) remains unclear. The objective of the present study was to investigate the protective effects of AR protein against 1-methyl-4-phenylpyridinium (MP

Protective Role of Transduced Tat-Thioredoxin1 (Trx1) against Oxidative Stress-Induced Neuronal Cell Death via ASK1-MAPK Signal Pathway

Oxidative stress plays a crucial role in the development of neuronal disorders including brain ischemic injury. Thioredoxin 1 (Trx1), a 12 kDa oxidoreductase, has anti-oxidant and anti-apoptotic functions in various cells. It has been highly implicated in brain ischemic injury. However, the protective mechanism of Trx1 against hippocampal neuronal cell death is not identified yet. Using a cell permeable Tat-Trx1 protein, protective mechanism of Trx1 against hydrogen peroxide-induced cell death was examined using HT-22 cells and an ischemic animal model. Transduced Tat-Trx1 markedly inhibited intracellular ROS levels, DNA fragmentation, and cell death in H2O2-treatment HT-22 cells. Tat-Trx1 also significantly inhibited phosphorylation of ASK1 and MAPKs in signaling pathways of HT-22 cells. In addition, Tat-Trx1 regulated expression levels of Akt, NE-kappa B, and apoptosis related proteins. In an ischemia animal model, Tat-Trx1 markedly protected hippocampal neuronal cell death and reduced astrocytes and microglia activation. These findings indicate that transduced Tat-Trx1 might be a potential therapeutic agent for treating ischemic injury

Transduced Tat-PRAS40 prevents dopaminergic neuronal cell death through ROS inhibition and interaction with 14-3-sigma protein

Proline rich Akt substrate (PRAS40) is a component of mammalian target of rapamycin complex 1 (mTORC1) and activated mTORC1 plays important roles for cellular survival in response to oxidative stress. However, the roles of PRAS40 in dopaminergic neuronal cell death have not yet been examined. Here, we examined the roles of Tat-PRAS40 in MPP+- and MPTP-induced dopaminergic neuronal cell death. Our results showed that Tat-PRAS40 effectively transduced into SH-SY5Y cells and inhibited DNA damage, ROS generation, and apoptotic signaling in MPP+-induced SH-SY5Y cells. Further, these protective mechanisms of Tat-PRAS40 protein display through phosphorylation of Tat-PRAS40, Akt and direct interaction with 14-3-3 sigma protein, but not via the mTOR-dependent signaling pathway. In a Parkinson's disease animal model, Tat-PRAS40 transduced into dopaminergic neurons in mouse brain and significantly protected against dopaminergic cell death by phosphorylation of Tat-PRAS40, Akt and interaction with 14-3-3 sigma protein. In this study, we demonstrated for the first time that Tat-PRAS40 directly protects against dopaminergic neuronal cell death. These results indicate that Tat-PRAS40 may provide a useful therapeutic agent against oxidative stress-induced dopaminergic neuronal cell death, which causes diseases such as PD