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(Delta 2/Delta 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 x 10(3) +/- 74.5 vs. 8.44 x 10(3) +/- 1.35 x 10(3), P < 0.01) in mouse substantia nigra, accompanied by loss of DA neurons (1.03 x 10(4) +/- 238 vs. 6.17 x 10(3) +/- 392, P < 0.001). Deficiency of JWA significantly aggravated reactive oxygen species (ROS) accumulation in substantia nigra compared with the wild-type mice. Increasing JWA expression in U251 glioma cells inhibited ROS with a concomitant increase in intracellular glutathione. Furthermore, suppression of IKKb-nuclear factor (NF)-kappa B 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-kappa B signaling pathway and is a potential treatment target for PD.