title: α-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death.
abstract: Abnormalities of α-synuclein (α-syn) and NMDA receptors (NMDARs) are implicated in the pathogenesis of Parkinson's disease. However, how these proteins interact with each other has not been elucidated. Here, the effect of α-syn on NMDARs was investigated by examining the alterations of surface NMDAR NR1 subunits in MES23.5 dopaminergic cells transfected with the human α-syn gene as well as in cells treated with extracellularly added human α-syn. As demonstrated previously that α-syn can enter cells in a non-endocytic manner without being degraded by the cellular proteolytic systems, the extracellularly added α-syn entered the cytoplasm of MES23.5 cells in a concentration-dependent manner. Both the α-syn-transfected cells and α-syn-treated cells exhibited increased intracellular α-syn levels and reduced surface NR1 without altering the total NR1. The α-syn-induced surface NR1 reduction was accompanied by suppression of NMDA-elicited intracellular Ca(2+) elevation and reductions of NMDA-induced caspase 3 activation and cell death, which was abolished by hypotonic shock and K(+) depletion, a procedure that blocks clathrin-mediated endocytosis, and by suppression of RAB5B expression with anti-RAB5B oligonucleotides. The data obtained provide evidence for the first time that α-syn may promote clathrin-mediated NMDAR endocytosis.
authors: Department of Neurobiology and the Sino-Japan Joint Laboratory on Neurodegenerative Diseases, Key Laboratory of Neurodegenerative Diseases (Capital Medical University), Ministry of Education, Xuanwu Hospital of China Capital Medical University, Beijing, China.
authors: Furong
authors: F
authors: Cheng
authors: Xin
authors: X
authors: Li
authors: Yaohua
authors: Y
authors: Li
authors: Chaodong
authors: C
authors: Wang
authors: Tao
authors: T
authors: Wang
authors: Guangwei
authors: G
authors: Liu
authors: Andrius
authors: A
authors: Baskys
authors: Kenji
authors: K
authors: Uéda
authors: Piu
authors: P
authors: Chan
authors: Shun
authors: S
authors: Yu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002966:Clathrin / Q000235:genetics / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004705:Endocytosis / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013778:Tetrazolium Salts; D013997:Time Factors; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D002966:Clathrin; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007381:Intermediate Filament Proteins; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D013778:Tetrazolium Salts; C430456:desmuslin; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D020696:rab5 GTP-Binding Proteins; D011188:Potassium; D002118:Calcium; D004298:Dopamine