Astrocytic JWA expression is essential to dopaminergic neuron survival in the pathogenesis of Parkinson's disease.

AIMS:To investigate the role of astrocytic JWA expression in dopaminergic (DA) neuron degeneration and in the pathogenesis of Parkinson's disease (PD). METHODS:Conditional astrocytic JWA null (JWA∆2/∆2/GFAP-Cre) mice and U251 glioma cells were used to evaluate the effects of JWA gene on DA neuron degeneration. The oxidative stress-driven molecular events were determined in both in vivo and in vitro models. RESULTS:Conditional astrocytic JWA knockout resulted in significant activation of astrocytes measured by increase in glial fibrillary acidic protein-positive cells (1.34×10(3)±74.5 vs. 8.44×10(3)±1.35×10(3), P<0.01) in mouse substantia nigra, accompanied by loss of DA neurons (1.03×10(4)±238 vs. 6.17×10(3)±392, P<0.001). Deficiency of JWA significantly aggravated reactive oxygen species accumulation in substantia nigra compared with the wild-type mice. Increasing JWA expression in U251 glioma cells inhibited with a concomitant increase in intracellular glutathione. Furthermore, suppression of IKKβ-nuclear factor (NF)-κB signaling pathway was shown to regulate JWA in a PD model. CONCLUSIONS:The JWA gene exerts neuroprotective roles against DA neuronal degeneration via modulating intracellular redox status and NF-κB signaling pathway and is a potential treatment target for PD.

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