β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins.
β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins.
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DOI：
10.1016/j.jbc.2021.101375
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Buchman VL
中科院分区：
文献类型：
--
作者：
Ninkina N;Millership SJ;Peters OM;Connor-Robson N;Chaprov K;Kopylov AT;Montoya A;Kramer H;Withers DJ;Buchman VL
突触核蛋白是神经元中高度表达的三种蛋白质的家族，主要已知α-突触核蛋白直接参与帕金森病和某些其他神经退行性疾病的病因学和发病机制，但其确切的生理功能仍不完全清楚。以前的研究已经证明α-突触核蛋白作为化学神经传递中涉及的各种机制的调节剂的重要性，但是关于突触前末梢内的分子过程中其他突触核蛋白家族成员β-突触核蛋白和γ-突触核蛋白的参与的信息是有限的。在这里，我们证明了从缺乏β-突触核蛋白的小鼠纹状体分离的突触囊泡的囊泡单胺转运体2依赖性多巴胺摄取显著减少。反过来，在体内或体外重新引入β-突触核蛋白而不是α-突触核蛋白或γ-突触核蛋白可改善三重α/β/γ-突触核蛋白缺陷型纹状体囊泡的摄取。我们还发现，黑质背侧部多巴胺能神经元对亚慢性给药帕金森病诱导前药1-甲基-4-苯基-1，2，3，6-四氢吡啶的抗性取决于β-突触核蛋白的存在，但仅当一种或两种其他突触核蛋白都不存在时。此外，突触核蛋白缺陷的突触囊泡与仅含有β-突触核蛋白的突触囊泡的蛋白质组学分析揭示了它们的蛋白质组成的差异。我们认为，所观察到的β-突触核蛋白对多巴胺摄取的增强作用可能是由突触囊泡的不同蛋白质结构引起的。这种结构变化也可能改善1-甲基-4-苯基吡啶鎓（1-甲基-4-苯基-1，2，3，6-四氢吡啶的毒性代谢物）的突触囊泡隔离，这将解释为什么表达β-突触核蛋白且缺乏α-突触核蛋白和/或γ-突触核蛋白的多巴胺能神经元对这种神经毒素具有抗性。
Synucleins, a family of three proteins highly expressed in neurons, are predominantly known for the direct involvement of α-synuclein in the etiology and pathogenesis of Parkinson's and certain other neurodegenerative diseases, but their precise physiological functions are still not fully understood. Previous studies have demonstrated the importance of α-synuclein as a modulator of various mechanisms implicated in chemical neurotransmission, but information concerning the involvement of other synuclein family members, β-synuclein and γ-synuclein, in molecular processes within presynaptic terminals is limited. Here, we demonstrated that the vesicular monoamine transporter 2–dependent dopamine uptake by synaptic vesicles isolated from the striatum of mice lacking β-synuclein is significantly reduced. Reciprocally, reintroduction, either in vivo or in vitro, of β-synuclein but not α-synuclein or γ-synuclein improves uptake by triple α/β/γ-synuclein–deficient striatal vesicles. We also showed that the resistance of dopaminergic neurons of the substantia nigra pars compacta to subchronic administration of the Parkinson's disease–inducing prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine depends on the presence of β-synuclein but only when one or both other synucleins are absent. Furthermore, proteomic analysis of synuclein-deficient synaptic vesicles versus those containing only β-synuclein revealed differences in their protein compositions. We suggest that the observed potentiation of dopamine uptake by β-synuclein might be caused by different protein architecture of the synaptic vesicles. It is also feasible that such structural changes improve synaptic vesicle sequestration of 1-methyl-4-phenylpyridinium, a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which would explain why dopaminergic neurons expressing β-synuclein and lacking α-synuclein and/or γ-synuclein are resistant to this neurotoxin.
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影响因子：
6.1
作者：
Klivenyi, P;Siwek, D;Beal, MF
通讯作者：
Beal, MF
影响因子：
4.6
作者：
Kopylov AT;Papysheva O;Gribova I;Kotaysch G;Kharitonova L;Mayatskaya T;Sokerina E;Kaysheva AL;Morozov SG
通讯作者：
Morozov SG
影响因子：
3.4
作者：
Burre, Jacqueline;Beckhaus, Tobias;Volknandt, Walter
通讯作者：
Volknandt, Walter
影响因子：
3.5
作者：
JAKES, R;SPILLANTINI, MG;GOEDERT, M
通讯作者：
GOEDERT, M
缺乏突触核蛋白家族的所有三个成员的小鼠中骨纹状体系统的功能改变。
DOI：
10.1523/jneurosci.6194-10.2011
发表时间：
2011-05-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Anwar S;Peters O;Millership S;Ninkina N;Doig N;Connor-Robson N;Threlfell S;Kooner G;Deacon RM;Bannerman DM;Bolam JP;Chandra SS;Cragg SJ;Wade-Martins R;Buchman VL
通讯作者：
Buchman VL