α-突触核蛋白通过上调内吞蛋白Rab5B促进海马神经元膜表面NMDA受体内在化

doi:10.3969/j.issn.1006-7795.2017.06.017

首都医科大学学报 ›› 2017, Vol. 38 ›› Issue (6): 863-867.doi: 10.3969/j.issn.1006-7795.2017.06.017

• Alpha-突触核蛋白的致病机制 • 上一篇下一篇

α-突触核蛋白通过上调内吞蛋白Rab5B促进海马神经元膜表面NMDA受体内在化

陈敏^1,2, 于文娇^1,3, 李昕^1,3,4,5, 杨巍巍^1,3,4,5, 李旭冉^1,3, 于顺^1,3,4,5

1. 首都医科大学宣武医院神经生物学研究室北京市老年病医疗研究中心, 北京 100053;
2. 桂林医学院附属医院神经科学实验室, 广西桂林 541001;
3. 首都医科大学帕金森病临床诊疗与研究中心, 北京 100053;
4. 帕金森病北京市重点实验室和教育部神经变性病重点实验室, 北京 100053;
5. 国家老年疾病临床医学研究中心, 北京 100053

收稿日期:2017-10-23 出版日期:2017-11-21 发布日期:2017-12-16
通讯作者: 于顺 E-mail:yushun103@163.com
基金资助:
国家自然科学基金（81371200，81071014，81401042），北京市医院管理局"使命"计划专项经费资助（SML20150803），北京市科学技术委员会资助（Z161100005116011，Z171100000117013），北京市卫生和计划生育委员会项目（PXM2017_026283_000002），广西自然科学基金（2014GXNSFAA118197）。

α-Synuclein promotes NMDA receptor internalization by upregulation of endocytosis protein Rab5B

Chen Min^1,2, Yu Wenjiao^1,3, Li Xin^1,3,4,5, Yang Weiwei^1,3,4,5, Li Xuran^1,3, Yu Shun^1,3,4,5

1. Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing Institute of Geriatrics, Beijing 100053, China;
2. Laboratory of Neuroscience, Affliliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Automous Region, China;
3. Clinical Center for Parkinson's Disease, Capital Medical University, Beijing 100053, China;
4. Beijing Key Laboratory for Parkinson's Disease and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing 100053, China;
5. National Clinical Research Center for Geriatric Disorders, Beijing 100053, China

Received:2017-10-23 Online:2017-11-21 Published:2017-12-16
Supported by:
This study was supported by National Natural Science Foundation of China (81371200, 81071014, 81401042), Beijing Municipal Administration of Hospitals' Mission Plan (SML20150803), Beijing Municipal Science & Technology Commission (Z161100005116011,Z171100000117013), Beijing Municipal Commission of Health and Family Planning (PXM2017_026283_000002), Natural Science Foundation of Guangxi (2014GXNSFAA118197).

摘要/Abstract

摘要： 目的研究α-突触核蛋白（α-synuclein，α-Syn）对N-甲基-D-天冬氨酸（N-methyl-D-aspartic acid receptors，NMDA）受体的调控及机制。方法在原代海马神经元，通过细胞外添加基因重组α-Syn和基因过表达α-Syn方法实现细胞内α-Syn含量增高，基因敲减技术抑制Rab5B，Western blotting法分析NMDA受体NR1亚单位和Rab5B表达。结果神经元内α-Syn含量增高可以使Rab5B表达上调，并降低膜表面NR1的水平；抑制Rab5B表达可有效反转α-Syn所致的膜表面NR1水平下降。结论 α-Syn通过上调Rab5B促进NMDA受体的内在化。

关键词: α-突触核蛋白, NMDA受体, 内在化, Rab5B, 海马神经元

Abstract: Objective To investigate the effect of α-synuclein (α-Syn) on surface N-methyl-D-aspartic acid receptors (NMDARs) in cultured rat hippocampal neurons.Methods Increased intracellular α-Syn was realized by extracellular addition of recombinant human α-Syn to the culture medium or transfection of human α-Syn gene to the neurons. Western blotting analysis was applied to observe the effects of α-Syn on levels of NMDA receptor NR1 subunit and Rab5B under conditions with or without Rab5B knockdown.Results Intracellular elevation of α-Syn decreased the surface expression of NMDA NR1 and cytoplasmic levels of Rab5B; Inhibition of Rab5B expression reversed the effects of α-Syn.Conclusion The accumulation of α-Syn in hippocampal neurons can promote the internalization of surface NMDARs through an endocytic mechanism that requires participation of Rab5B.

Key words: α-synuclein, NMDA receptor, internalization, Rab5B, hippocampal neurons

中图分类号:

Q189

陈敏, 于文娇, 李昕, 杨巍巍, 李旭冉, 于顺. α-突触核蛋白通过上调内吞蛋白Rab5B促进海马神经元膜表面NMDA受体内在化[J]. 首都医科大学学报, 2017, 38(6): 863-867.

Chen Min, Yu Wenjiao, Li Xin, Yang Weiwei, Li Xuran, Yu Shun. α-Synuclein promotes NMDA receptor internalization by upregulation of endocytosis protein Rab5B[J]. Journal of Capital Medical University, 2017, 38(6): 863-867.

参考文献

[1] Shrivastava A N, Aperia A, Melki R, et al. Physico-pathologic mechanisms involved in neurodegeneration:misfolded protein-plasma membrane interactions[J]. Neuron, 2017,95(1):33-50.
[2] McCann H, Cartwright H, Halliday G M. Neuropathology of alpha-synuclein propagation and braakhypothesis[J]. Mov Disord, 2016(31):152-160.
[3] Aarsland D, Andersen K, Larsen J P, et al. Risk of dementia in Parkinson's disease[J]. Neurology, 2001, 56:730-736.
[4] Visvanathan R. Dementia with Lewy bodies[J]. J Clin Neurosci, 2004, 11(6):573-576.
[5] Lim Y, Kehm V M, Lee E B, et al.α-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies[J].J Neurosci, 2011, 31(27):10076-10087.
[6] Sardi S P, Clarke J, Kinnecom C, et al.CNS expression of glucocerebrosidase corrects alpha-Synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy[J]. Proc Natl AcadSci U S A, 2011, 108(29):12101-12106.
[7] Diógenes M J, Dias R B, Rombo D M, et al.Extracellular alpha-Synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation[J]. J Neurosci, 2012, 32(34):11750-11762.
[8] Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity:impact on receptor properties, synaptic plasticity and disease[J]. Nat Rev Neurosci, 2013, 14(6):383-400.
[9] Shi M M, Shi C H, Xu Y M. RabGTPases:the key players in the molecular pathway of parkinson's disease[J]. Front Cell Neurosci, 2017, 11:81.
[10] Arnett A L, Bayazitov I, Blaabjerg M, et al. Antisenseoligonucleotide against GTPase Rab5b inhibits metabotropic agonist DHPG-inducedneuroprotection[J]. Brain Res, 2004, 1028(1):59-65.
[11] 殷娟娟, 韩俊燕, 李昕, 等. α-突触核蛋白功能片段向多巴胺能神经细胞内的转运及其对细胞增殖的影响[J]. 首都医科大学学报, 2007, 28(3):345-349.
[12] Cheng F, Li X, Li Y, et al. alpha-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death[J]. J Neurochem, 2011, 119(4):815-825.
[13] Hanson J E, Pare J F, Deng L, et al. Altered GluN2B NMDA receptor function and synaptic plasticity during early pathology in the PS2APP mouse model of alzheimer's disease[J]. Neurobiol Dis, 2015, 74:254-262.
[14] Wang Q, Li J, Wei X, et al. Alterations of NMDA receptor binding in various brain regions among 6-hydroxydopamine-induced Parkinsonian rats[J]. Int J Neurosci, 2014, 124(6):457-465.

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α-突触核蛋白通过上调内吞蛋白Rab5B促进海马神经元膜表面NMDA受体内在化

α-Synuclein promotes NMDA receptor internalization by upregulation of endocytosis protein Rab5B

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