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《CNS Neuroscience & Therapeutics》 8:754-762 (2014)

Astrocytic JWA Expression is Essential to Dopaminergic Neuron Survival in the Pathogenesis of Parkinson's Disease

Miao, Shu-Han; Sun, Hong-Bin; Ye, Yang; Yang, Jing-Jing; Shi, Yao-Wei; Lu, Ming; Hu, Gang; Zhou, Jian-Wei

Abstract:

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 (JWAΔ2/Δ2/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 9 103  74.5 vs. 8.44 9 103  1.35 9 103, P < 0.01) in mouse substantia nigra, accompanied by loss of DA neurons (1.03 9 104  238 vs. 6.17 9 103  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)-jB 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-jB signaling pathway and is a potential treatment target for PD.