Mechanism of stress-induced attacks in an episodic neurologic disorder.
Mechanism of stress-induced attacks in an episodic neurologic disorder.
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DOI：
10.1126/sciadv.abh2675
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发表时间：
2022-04-22
期刊：
影响因子：
13.6
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中科院分区：
文献类型：
--
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压力是发作性神经系统疾病中最常见的诱因。在发作性共济失调2型（EA 2）中，身体或情绪压力会导致严重的运动功能障碍发作，表现为共济失调和肌张力障碍。我们使用蹒跚（tg/tg）小鼠，一个忠实的动物模型EA 2，解剖的机制，应激诱导的运动攻击。我们发现，在急性应激反应中，去甲肾上腺素激活浦肯野细胞上的α1-肾上腺素能受体（α1-Rs），导致其不稳定的放电，从而导致运动发作。我们发现去甲肾上腺素通过酪蛋白激酶2（CK 2）依赖性信号通路破坏浦肯野细胞的自发性内在起搏，从而诱导浦肯野细胞的不稳定放电，这可能会降低钙依赖性钾通道的活性。此外，我们报告说，在一些节点中断这种信号级联，防止压力引起的攻击摇摇欲坠的鼠标。总之，我们的研究结果表明，去甲肾上腺素和CK 2需要启动EA 2的应激诱导的攻击，并提供以前未确定的治疗干预的目标。应激诱导的EA 2攻击由浦肯野细胞SK通道的去甲肾上腺素能α1-Rs和CK 2依赖性磷酸化介导。
Stress is the most common trigger among episodic neurologic disorders. In episodic ataxia type 2 (EA2), physical or emotional stress causes episodes of severe motor dysfunction that manifest as ataxia and dystonia. We used the tottering (tg/tg) mouse, a faithful animal model of EA2, to dissect the mechanisms underlying stress-induced motor attacks. We find that in response to acute stress, activation of α1-adrenergic receptors (α1-Rs) on Purkinje cells by norepinephrine leads to their erratic firing and consequently motor attacks. We show that norepinephrine induces erratic firing of Purkinje cells by disrupting their spontaneous intrinsic pacemaking via a casein kinase 2 (CK2)–dependent signaling pathway, which likely reduces the activity of calcium-dependent potassium channels. Moreover, we report that disruption of this signaling cascade at a number of nodes prevents stress-induced attacks in the tottering mouse. Together, our results suggest that norepinephrine and CK2 are required for the initiation of stress-induced attacks in EA2 and provide previously unidentified targets for therapeutic intervention. Stress-induced attacks in EA2 are mediated by noradrenergic α1-Rs and CK2-dependent phosphorylation of Purkinje cell SK channels.
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