Phosphatase and tensin homologue: a therapeutic target for SMA.
Phosphatase and tensin homologue: a therapeutic target for SMA.
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DOI：
10.1038/sigtrans.2017.38
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发表时间：
2017
影响因子：
39.3
通讯作者：
Ning K
中科院分区：
文献类型：
--
作者：
Godena VK;Ning K
脊髓性肌萎缩症（SMA）是最常见的青少年神经退行性疾病之一，可与儿童死亡率相关。SMA是由广泛表达的基因运动神经元生存基因1（SMN 1）突变引起的，导致SMN蛋白减少和运动神经元死亡。这种疾病是无法治愈的，唯一的治疗策略是提高运动神经元中SMN蛋白水平的表达。SMA小鼠和SMA培养物中大量的运动神经元是半胱天冬酶阳性的，具有浓缩的核，表明这些细胞易于发生称为细胞凋亡的细胞死亡过程。寻找对中枢神经系统（CNS）损伤具有神经保护作用的其他潜在分子或信号通路对于扩大发育医学的范围至关重要。PTEN是一种磷酸酶和张力蛋白同源物，是一种肿瘤抑制因子，广泛表达于中枢神经系统。PTEN缺失激活抗凋亡因子，并且很明显，该途径在许多神经退行性疾病中起重要的保护作用。它作为PIP 3/AKT通路的负调节剂发挥作用，从而通过脂质磷酸酶活性调节其下游细胞功能。此外，来自我们小组的先前报告表明，在SMN delta 7小鼠中使用病毒载体递送系统的PTEN去除减少了疾病病理，显著挽救了SMA小鼠的存活率和体重。因此，敲除/缺失/突变PTEN和操纵PTEN介导的Akt/PKB信号通路可能是促进SMA运动神经元存活的重要治疗策略。
Spinal muscular atrophy (SMA) is one of the most common juvenile neurodegenerative diseases, which can be associated with child mortality. SMA is caused by a mutation of ubiquitously expressed gene, Survival Motor Neuron1 (SMN1), leading to reduced SMN protein and the motor neuron death. The disease is incurable and the only therapeutic strategy to follow is to improve the expression of SMN protein levels in motor neurons. Significant numbers of motor neurons in SMA mice and SMA cultures are caspase positive with condensed nuclei, suggesting that these cells are prone to a process of cell death called apoptosis. Searching for other potential molecules or signaling pathways that are neuroprotective for central nervous system (CNS) insults is essential for widening the scope of developmental medicine. PTEN, a Phosphatase and Tensin homologue, is a tumor suppressor, which is widely expressed in CNS. PTEN depletion activates anti-apoptotic factors and it is evident that the pathway plays an important protective role in many neurodegenerative disorders. It functions as a negative regulator of PIP3/AKT pathway and thereby modulates its downstream cellular functions through lipid phosphatase activity. Moreover, previous reports from our group demonstrated that, PTEN depletion using viral vector delivery system in SMN delta7 mice reduces disease pathology, with significant rescue on survival rate and the body weight of the SMA mice. Thus knockdown/depletion/mutation of PTEN and manipulation of PTEN medicated Akt/PKB signaling pathway may represent an important therapeutic strategy to promote motor neuron survival in SMA.
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