title: Astrocytic JWA expression is essential to dopaminergic neuron survival in the pathogenesis of Parkinson's disease.
abstract: OBJECTIVE
  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 (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 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.
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Shu-Han
authors.initials: SH
authors.lastname: Miao
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Sun
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Yang
authors.forename: Yao-Wei
authors.initials: YW
authors.lastname: Shi
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Zhou
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006360:Heat-Shock Proteins; D006719:Homovanillic Acid / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D020267:MPTP Poisoning / Q000473:pathology*; D026901:Membrane Transport Proteins; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000473:pathology; D014162:Transfection
chemical_list: C464502:Arl6ip5 protein, mouse; D002352:Carrier Proteins; D005904:Glial Fibrillary Acidic Protein; D006360:Heat-Shock Proteins; D026901:Membrane Transport Proteins; D017382:Reactive Oxygen Species; D015102:3,4-Dihydroxyphenylacetic Acid; D051550:I-kappa B Kinase; D005978:Glutathione; D004298:Dopamine; D006719:Homovanillic Acid
keywords: Dopamine; JWA; NF-κB; Parkinson's disease; Reactive oxygen species