Targeting β-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson's disease
Targeting β-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson's disease
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DOI：
10.1073/pnas.1502740112
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发表时间：
2015-05-12
影响因子：
11.1
通讯作者：
Caron, Marc G.
中科院分区：
文献类型：
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作者：
Urs, Nikhil M.;Bido, Simone;Caron, Marc G.
帕金森病 (PD) 的特点是严重的运动缺陷，通常用多巴胺 (DA) 前体 L-3,4-二羟基苯丙氨酸 (L-DOPA) 进行治疗，但长期使用会导致运动障碍，称为 L-DOPA 诱发的运动障碍 (LID)。最近对 PD 动物模型的研究表明，运动障碍与 G 蛋白介导的 DA 受体信号传导过度激活有关。 beta-Arrestins 除了激活其自身的 G 蛋白独立信号传导事件（已被证明可以介导运动）之外，还可以使 DA 受体（D1R 和 D2R）上的 G 蛋白信号传导脱敏。因此，在 PD L-DOPA 治疗中靶向 β-arrestins 可能被证明是一种理想的方法。在这里，我们在帕金森症状的双侧 DA 耗竭小鼠模型中表明，β-arrestin2 的基因缺失显着限制了有益的运动效应，同时显着增强了急性或慢性左旋多巴治疗的运动障碍样效应。在敲除小鼠或对照小鼠中进行病毒拯救或过度表达 β-arrestin2 可以逆转或预防 LID 及其关键生化标记物。在其他更传统的 DA 神经元丢失和 PD 动物模型中，例如 6-羟基多巴胺治疗的小鼠或大鼠以及 1-甲基-4-苯基-1,2,3,6-四氢吡啶治疗的非人灵长类动物，β-arrestin2 过度表达显着减少运动障碍，同时保持左旋多巴的治疗效果。制药行业正在投入大量精力来寻找阻断 PD 患者 LID 的治疗方法。我们的结果指出了一种潜在的治疗方法，即开发遗传或药理学干预来增强 β-arrestin2 或限制 G 蛋白依赖性 D1/D2R 信号传导可能代表一种更机械化的策略。
Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes dyskinesias referred to as L-DOPA-induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G proteinmediated signaling through DA receptors. beta-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting beta-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of beta-arrestin2 significantly limits the beneficial locomotor effectswhilemarkedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of beta-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated non-human primates, beta-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance beta-arrestin2-or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.