ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target.
ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target.
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大脑中的ABCC9/SUR2：对海马硬化的衰老和潜在治疗靶标的影响。
DOI：
10.1016/j.arr.2015.07.007
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发表时间：
2015-11
影响因子：
13.1
通讯作者：
Fardo DW
中科院分区：
文献类型：
--
作者：
Nelson PT;Jicha GA;Wang WX;Ighodaro E;Artiushin S;Nichols CG;Fardo DW
ABCC9 基因及其多肽产物 SUR2 越来越多地与人类神经系统疾病有关，包括老年脑部的流行疾病。 SUR2 蛋白是 ATP 敏感钾 (“KATP”) 通道的组成部分，这是一种压力和/或缺氧的代谢传感器，已被证明会随着衰老而发生变化。 KATP 通道还有助于调节神经血管单位。大多数脑细胞类型都表达 SUR2，包括神经元、星形胶质细胞、少突胶质细胞、小胶质细胞、血管平滑肌、周细胞和内皮细胞。因此，ABCC9 基因变异与人类脑部疾病风险相关也就不足为奇了。例如，Cantu 综合征是 ABCC9 突变的结果；我们讨论这种遗传综合征的神经系统表现。与 ABCC9 基因变异相关的更常见的脑部疾病包括衰老性海马硬化症 (HS-Aging)、睡眠障碍和抑郁症。 HS-Aging 是一种常见的神经系统疾病，具有神经退行性（异常 TDP-43）和脑血管（动脉硬化）疾病的病理特征。至于潜在的治疗干预，人类药典同时包含 SUR2 激动剂和拮抗剂，因此 ABCC9/SUR2 可能提供一个“可用药靶点”，可能与 HS-Aging 和阿尔茨海默病相关。我们的结论是，需要做更多的工作来更好地了解 ABCC9/SUR2 在健康和疾病条件下在人脑中的作用。
The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“KATP”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a “druggable target”, relevant perhaps to both HS-Aging and Alzheimer’s disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions.