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Sci Rep. 2016 Jun 27;6:28823. doi: 10.1038/srep28823.

DJ-1 deficiency impairs glutamate uptake into astrocytes via the regulation of flotillin-1 and caveolin-1 expression.

Kim JM1,2, Cha SH1,2, Choi YR1,2,3, Jou I1,2,3, Joe EH1,2,3, Park SM1,2,3.

Author information

1
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.
2
Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
3
Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.

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.

PMID:
27346864
PMCID:
PMC4922019
DOI:
10.1038/srep28823
[Indexed for MEDLINE]
Free PMC Article

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