Gpx4 and ferroptosis inhibition in retarding ALS

肌萎缩侧索硬化症（Amyotrophic Lateral Sclerosis，ALS）是最常见的运动神经元退行性变 运动神经元变性和死亡导致进行性瘫痪的疾病， 最终死于呼吸衰竭。ALS是退伍军人特别关注的几项研究 表明服兵役与ALS风险增加有关。目前没有 有效治疗这种使人衰弱的疾病和开发有效的治疗方法， 由于缺乏合适的靶点，特别是对于散发性ALS， 大多数病例没有可识别的遗传原因。谷胱甘肽过氧化物酶4（Gpx 4）是一种 硒蛋白谷胱甘肽过氧化物酶在保护膜免受氧化损伤中的重要作用 损害最近，Gpx 4被鉴定为铁凋亡的关键抑制剂，铁凋亡是一种氧化性铁- 依赖性细胞死亡机制不同于其他细胞死亡机制，如凋亡。 我们偶然发现Gpx 4是脊髓运动神经元的关键保护者。此外，本发明还提供了一种方法， 我们的初步结果表明Gpx 4的过表达延长了ALS小鼠的寿命。我们 初步结果进一步表明，Gpx 4的铁凋亡抑制功能是重要的 运动神经元保护基于这些令人兴奋的结果，该项目旨在测试 Gpx 4过表达和铁凋亡抑制对ALS的治疗潜力。整体 在本项目中要检验假设是：Gpx 4过表达和铁凋亡抑制可以 改善运动神经元变性，延缓ALS的发病。假设将被检验 三个具体目标。目的1是确定Gpx 4过表达是否改善运动功能， 功能和减弱ALS小鼠的运动神经元变性。目标2是研究 铁凋亡抑制在延缓ALS小鼠疾病中的作用。目的3是确定Gpx 4的作用 通过病毒递送介导的过表达延缓ALS小鼠的疾病。结果是 该项目将为ALS运动神经元变性机制提供新的见解， 重要的是，这可能会导致ALS的新治疗策略。

Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron degenerative disease, in which motor neuron degeneration and death result in progressive paralysis and eventual death by respiratory failure. ALS is a particular concern for veterans as several studies indicated that military service is associated with increased risk of ALS. At present, there are no effective treatments for this debilitating disease and the development of effective therapies is impeded by the lack of suitable targets, particularly for sporadic ALS, which represents the majority cases that do not have identifiable genetic causes. Glutathione peroxidase 4 (Gpx4) is a selenoprotein glutathione peroxidase important in protecting membranes against oxidative damage. Recently, Gpx4 was identified as a key inhibitor of ferroptosis, an oxidative, iron- dependent cell death mechanism different from other cell death mechanisms such as apoptosis. Serendipitously, we discovered that Gpx4 is a key protector of spinal motor neurons. In addition, our preliminary results indicated that overexpression of Gpx4 extended lifespan of ALS mice. Our preliminary results further suggested that the ferroptosis inhibition function of Gpx4 is important for motor neuron protection. Built upon these exciting results, this project is designed to test the therapeutic potential of Gpx4 overexpression and ferroptosis inhibition for ALS. The overall hypothesis to be tested in this project is: Gpx4 overexpression and ferroptosis inhibition can ameliorate motor neuron degeneration and retard disease of ALS. The hypothesis will be tested by three specific aims. Aim 1 is to determine whether Gpx4 overexpression improves locomotor function and attenuates motor neuron degeneration in ALS mice. Aim 2 is to examine the role of ferroptosis inhibition in retarding disease in ALS mice. Aim 3 is to determine the effect of Gpx4 overexpression mediated by viral delivery in retarding disease of ALS mice. The results from this project will provide novel insights into the mechanism of motor neuron degeneration in ALS, and importantly, could lead to new therapeutic strategies for ALS.