Investigation of Ferroptosis as a Therapeutic Target for ALS

肌萎缩侧索硬化症(ALS)是一种毁灭性的运动神经元退行性疾病，可导致 瘫痪和最终死亡。肌萎缩侧索硬化症是退伍军人特别关注的问题，因为服兵役与 肌萎缩侧索硬化症风险增加。ALS的根本原因是运动神经元的死亡；然而，运动的形式 肌萎缩侧索硬化症中的神经元死亡仍不清楚。铁下垂是一种氧化性、铁依赖的细胞死亡机制。结果 我们之前的研究表明，运动神经元很容易受到铁性下垂的影响。重要的是，我们展示了 最近，加强了对铁性下垂的防御，显著延长了寿命，改善了 在广泛使用的ALS小鼠模型SOD1G93A小鼠中，运动神经元变性表明铁下垂是 运动神经元的目标脆弱性。然而，目前关于铁性上睑下垂在 肌萎缩侧索硬化症的运动神经元死亡仍然没有答案。例如，目前尚不清楚抑制铁性下垂是否在 症状期可以延缓运动神经元病的进展，以及铁上性应激对运动神经元病的影响 不同细胞类型在运动神经元病发病机制中的作用尚不清楚。为了回答这些问题，我们 已经产生了一种新的小鼠模型，该模型具有铁性下垂的主要防御者Gpx4的诱导表达， 这使得我们可以通过时间和细胞类型的特定方式从基因上抑制铁下垂。在我们的 初步研究，我们还鉴定了一种小分子化合物，具有延缓下垂的能力。 活体运动神经元。为了确定铁下垂抑制化合物是否可以延缓运动神经元病，我们 将在SOD1G93A小鼠身上测试该化合物的疗效。在这个项目中检验的总体假设是： 在发病后抑制铁性下垂将有效地延缓运动神经元病的进展和 铁下垂抑制以一种特定细胞类型的方式延缓运动神经元疾病。这个项目的结果是 将为肌萎缩侧索硬化症运动神经元变性的机制提供新的见解，更重要的是，可以 为肌萎缩侧索硬化症带来新的治疗策略。

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron degenerative disease that leads to paralysis and eventual death. ALS is a particular concern for veterans, as military service is associated with increased risk of ALS. The root cause of ALS is the death of motor neurons; however, the modalities of motor neuron death in ALS remain unclear. Ferroptosis is an oxidative, iron-dependent cell death mechanism. Results from our prior research have shown that motor neurons are vulnerable to ferroptosis. Importantly, we showed recently that increased defense against ferroptosis resulted in significantly increased lifespan and ameliorated motor neuron degeneration in SOD1G93A mice, a widely used ALS mouse model, indicating that ferroptosis is a targetable vulnerability of motor neurons. However, at present, key questions about the roles of ferroptosis in motor neuron death of ALS remain unanswered. For example, it is unclear whether inhibition of ferroptosis at symptomatic stage can retard progression of motor neuron disease, and the contributions of ferroptotic stress of different cell types on pathogenesis of motor neuron disease remain unknown. To answer those questions, we have generated a novel mouse model with inducible expression of Gpx4, the master defender of ferroptosis, which allows us to inhibit ferroptosis genetically in both temporal and cell-type specific manners. In our preliminary study, we have also identified a small molecule compound with the ability to retard ferroptosis of motor neurons in vivo. To determine if ferroptosis-inhibiting compounds can retard motor neuron disease, we will test the efficacy of this compound in SOD1G93A mice. The overall hypothesis tested in this project is: inhibition of ferroptosis after disease onset will be effective in retarding progression of motor neuron disease and ferroptosis inhibition retards motor neuron disease in a cell-type specific manner. The results from this project will provide novel insights into the mechanisms of motor neuron degeneration of ALS, and importantly, could lead to new therapeutic strategies for ALS.