title: DJ-1 deficiency impairs glutamate uptake into astrocytes via the regulation of flotillin-1 and caveolin-1 expression.
abstract: Parkinson's disease (PD) is a common chronic and progressive neurodegenerative disorder. Although the cause of PD is still poorly understood, mutations in many genes including SNCA, parkin, PINK1, LRRK2, and DJ-1 have been identified in the familial forms of PD. It was recently proposed that alterations in lipid rafts may cause the neurodegeneration shown in PD. Here, we observe that DJ-1 deficiency decreased the expression of flotillin-1 (flot-1) and caveolin-1 (cav-1), the main protein components of lipid rafts, in primary astrocytes and MEF cells. As a mechanism, DJ-1 regulated flot-1 stability by direct interaction, however, decreased cav-1 expression may not be a direct effect of DJ-1, but rather as a result of decreased flot-1 expression. Dysregulation of flot-1 and cav-1 by DJ-1 deficiency caused an alteration in the cellular cholesterol level, membrane fluidity, and alteration in lipid rafts-dependent endocytosis. Moreover, DJ-1 deficiency impaired glutamate uptake into astrocytes, a major function of astrocytes in the maintenance of CNS homeostasis, by altering EAAT2 expression. This study will be helpful to understand the role of DJ-1 in the pathogenesis of PD, and the modulation of lipid rafts through the regulation of flot-1 or cav-1 may be a novel therapeutic target for PD.
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Jin-Mo
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Seon-Heui
authors.initials: SH
authors.lastname: Cha
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.|Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Yu Ree
authors.initials: YR
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.|Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.|Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Joe
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.|Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Sang Myun
authors.initials: SM
authors.lastname: Park
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism*; D002490:Central Nervous System; D002784:Cholesterol / Q000378:metabolism; D004705:Endocytosis; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D006706:Homeostasis; D021962:Membrane Microdomains; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1 / Q000172:deficiency* / Q000235:genetics*
chemical_list: D051242:Caveolin 1; D027342:Excitatory Amino Acid Transporter 2; D008565:Membrane Proteins; C493396:Slc1a2 protein, mouse; C106354:flotillins; D018698:Glutamic Acid; D002784:Cholesterol; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1