Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington's disease
Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington's disease
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钙调节缺陷在亨廷顿病心肺功能障碍中的作用
DOI：
10.1172/jci.insight.140614
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发表时间：
2020-10-02
期刊：
影响因子：
8
通讯作者：
Marks, Andrew R.
中科院分区：
文献类型：
--
作者：
Dridi, Haikel;Liu, Xiaoping;Marks, Andrew R.
亨廷顿氏病（HD）是一种累及纹状体神经元的进行性常染色体显性神经退行性疾病，发病于年轻人，伴有肌肉协调性丧失和认知能力下降。人们不太了解的是，HD患者还表现出心脏和呼吸功能障碍，包括肺功能不全和心律失常。这些症状的潜在机制尚不清楚。在目前的研究中，我们提供了HD的心肺功能障碍的原因，并确定了一个潜在的新的治疗靶点。我们现在表明，通过翻译后修饰的ryanodine受体/细胞内钙释放（RyR）通道，细胞内钙（Ca2+）泄漏在HD病理中起重要作用。在HD患者和HD小鼠模型中，RyR通道被氧化，PKA磷酸化，并在脑、心脏和隔膜中泄漏（Q175）。内质网Ca2+泄漏的HD小鼠（Q175）表现出认知功能障碍，与心律失常相关的副交感神经张力下降，膈肌收缩功能降低，导致呼吸功能受损。认知、运动和呼吸功能的缺陷通过一种新型Rycal小分子药物（S107）治疗得到改善，该药物可以修复泄漏的RyR。因此，漏性ryr可能在HD的神经元、心脏和膈肌病理生理中发挥作用，并且ryr是一个潜在的新的治疗靶点。
Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder affecting striatal neurons beginning in young adults with loss of muscle coordination and cognitive decline. Less appreciated is the fact that patients with HD also exhibit cardiac and respiratory dysfunction, including pulmonary insufficiency and cardiac arrhythmias. The underlying mechanism for these symptoms is poorly understood. In the present study we provide insight into the cause of cardiorespiratory dysfunction in HD and identify a potentially novel therapeutic target. We now show that intracellular calcium (Ca2+) leak via posttranslationally modified ryanodine receptor/intracellular calcium release (RyR) channels plays an important role in HD pathology. RyR channels were oxidized, PKA phosphorylated, and leaky in brain, heart, and diaphragm both in patients with HD and in a murine model of HD (Q175). HD mice (Q175) with endoplasmic reticulum Ca2+ leak exhibited cognitive dysfunction, decreased parasympathetic tone associated with cardiac arrhythmias, and reduced diaphragmatic contractile function resulting in impaired respiratory function. Defects in cognitive, motor, and respiratory functions were ameliorated by treatment with a novel Rycal small-molecule drug (S107) that fixes leaky RyR. Thus, leaky RyRs likely play a role in neuronal, cardiac, and diaphragmatic pathophysiology in HD, and RyRs are a potential novel therapeutic target.