The dysfunction of nuclear TDP-43 is recently implicated in neurodegenerative diseases. However, how this nuclear protein plays its role in normal conditions and in other neurological disorders such as ischemic stroke remains unclear. To reveal the role of TDP-43 in neuronal injury and its underlying molecular mechanisms, we have employed a glutamate neurototoxicity-induced neuronal injury model by treating cultured mouse cortical neurons with DL-threo-beta- hydroxyaspartate (THA), an inhibitor of glutamate transporters. We obtained the first evidence that the expression of nuclear TDP-43 was enhanced in cortical neurons at the early stage after THA- induced glutamate accumulation. Interestingly, we found that the activation of NR2A-containing NMDA receptors (NR2ARs) and subsequent downregulation of phosphatase PTEN contributed to the increase of TDP-43 in the nucleus. We also demonstrated that the NR2AR/PTEN/TDP-43 pathway is neuroprotective in THA-induced neuronal injury and that TDP-43 knockdown promoted neuronal death in ischemic neuronal injury. In the present project, we plan to first determine the neuroprotective role of NR2AR/PTEN/TDP-43 pathway in ischemic neuronal injury in both in vitro and in vivo ischemic models. We will then determine the cellular and molecular mechanisms whereby NR2AR, PTEN and TDP-43 act in a common pathway to exert their neuroprotective effect. This study will not only establish the neuroprotective role of TDP-43 in the nucleus but also reveal the novel molecular mechanisms by which NR2AR and PTEN exert their effects on neuronal survival/death through TDP-43-dependent nuclear signaling. We expect that the molecular evidence obtained in this project would ultimately promote the development of novel neuroprotection strategy for the treatment of stroke patients.
Stroke is the major cause of death and disability across the world and in the US in particular. But there are no effective therapies available. The proposed research will establish the neuroprotective role of TDP-43 protein in nucleus and also reveal the molecular mechanisms whereby NR2A- containing NMDA receptors and PTEN downregulation play their neuroprotective roles through TDP- 43-dependent nuclear signaling. The molecular evidence obtained in this project would promote the development of a novel neuroprotection strategy for the treatment of ischemic stroke.
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|Hu, Rong; Chen, Juan; Lujan, Brendan et al. (2016) Glycine triggers a non-ionotropic activity of GluN2A-containing NMDA receptors to confer neuroprotection. Sci Rep 6:34459|