Preserving mitochondrial function for alleviating ALS progression

项目摘要 肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种无法治愈的致命性神经肌肉疾病。大多数ALS是散发性的 没有明确的遗传原因。然而，脊髓和肌肉尸检/活检样本， 散发性和家族性ALS患者均表现出明显的形态学和生化特性缺陷 of mitochondria线粒体.这表明异常线粒体是神经肌肉变性的常见参与者 尽管有病因学在过去的12年里，我们使用ALS小鼠模型（G93 A）进行的研究建立了一个 骨骼肌线粒体功能障碍是ALS发病机制的一部分。肌肉出现 是ALS突变的主要目标，除了成为神经元退缩的受害者，因为 肌萎缩侧索硬化症中肌反馈到神经肌肉接头（NMJ）重塑的线粒体缺陷。因此，在本发明中， 线粒体功能的恢复是减轻ALS的全身症状的合乎逻辑的方法， 解决一个共同的问题我们做了一个新的discocery，ALS进展包括一个泄漏的肠道， G93 A小鼠中的微生物组不平衡（生态失调）。这种肠道缺陷发生在ALS发病之前 神经肌肉症状，表明肠道缺陷可能在ALS进展中起作用。我们报道了 G93 A小鼠的结肠含有较少的丁酸盐产生细菌， 减轻G93 A小鼠的肠道缺陷，改善其神经肌肉性能并延长其寿命。 因此，我们的研究带来了一个新的概念，即恢复肠道内稳态可能提供一种替代手段， 改善神经肌肉功能以治疗ALS。自最初提交以来，我们与Brotto的合作 实验室有了几个令人兴奋的新发现。我们确定了ROS相关生物活性物质的脂质组学特征改变， 在G93 A小鼠中通过一个月的丁酸盐饮食补充恢复的肌肉中的脂质（BL）。此外，本发明还 丁酸盐处理直接增强肌肉收缩力。我们的初步数据还显示丁酸盐 治疗改善了G93 A中线粒体功能及其对氧化应激诱导的损伤的敏感性 肌肉纤维我们的数据表明，丁酸可能是一个重要的介质调节神经肌肉肠道 整合生理学我们假设，神经肌肉系统和 肠道有助于ALS中线粒体功能的进行性丧失，以及丁酸盐的恢复。 相关微生物组在保护线粒体功能以治疗ALS方面具有益处。的 拟议的研究将解决两个基本问题：肠道缺陷如何有助于线粒体 ALS的神经肌肉系统功能障碍（目的1）？神经肌肉-肠道信号能被用来 改善线粒体功能以减缓ALS进展和/或改善ALS患者的生活质量（目的 2）？虽然肠道内稳态和微生物组的改变与ALS的人类病理学有关， 我们的研究将为ALS研究领域带来新的概念。从本研究中获得的知识 可能对开发对抗ALS的新治疗策略具有潜在的转化意义。

Project Summary Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease without cure. Most ALS are sporadic cases without identified genetic causes. However, the spinal cord and muscle autopsy/biopsy samples from both sporadic and familial ALS patients all show remarkable defects in morphology and biochemical properties of mitochondria. This indicates abnormal mitochondria as a common player in neuromuscular degeneration despite the etiology. Our research using the ALS mouse models (G93A), over the last 12 years, establishes a concept that mitochondrial dysfunction in skeletal muscle is part of the pathogenesis of ALS. Muscle appears to be a primary target of ALS mutation, in addition to being victim of neuronal withdrawal, because mitochondrial defects in muscle feedback to neuromuscular junction (NMJ) remodeling in ALS. Thus, restoration of mitochondrial function is a logical approach to alleviate the systemic symptom of ALS through fixing a common pathology. We made a novel discocery that ALS progression includes a leaky gut with an imbalanced microbiome (dysbiosis) in G93A mice. This gut defects occurs before the onset of ALS neuromuscular symptoms, suggesting that gut defects may play a role in ALS progression. We reported that the colon of G93A mice contained less butyrate-producing bacteria, and the dietary butyrate supplementation alleviated gut defects in G93A mice, improving their neuromuscular performance and extending their life span. Thus, our study brought a new concept that restoring gut homeostasis may provide an alternative means for improving neuromuscular function to treat ALS. Since the original submission, our collaboration with the Brotto Lab made several exciting new discoveries. We identified altered Lipidomics Profiles of ROS-related Bioactive Lipids (BLs) in muscle that were restored by one-month butyrate diet supplementation in G93A mice. Further, butyrate treatment directly enhanced muscle contractility. Our preliminary data also show that butyrate treatment improved mitochondrial function and its susceptibility to oxidative-stress induced damage in G93A muscle fibers. Our data suggest that butyrate could be an important mediator regulating the neuromuscular-gut integrative physiology. We hypothesize that integrative signaling between the neuromuscular system and gut contributes to the progressive loss of mitochondrial function in ALS, and restoration of butyrate- related microbiome has benefits in preserving mitochondrial function for treatment of ALS. The proposed study will address two fundamental questions: How do gut defects contribute to mitochondrial dysfunction of neuromuscular system in ALS (Aim 1)? Can neuromuscular-gut signaling be leveraged to improve mitochondrial function to slow ALS progression and/or improve the life quality of ALS patients (Aim 2)? While altered intestinal homeostasis and microbiome is linked to the human pathology of ALS, we anticipate that our study will bring novel concepts to the ALS research field. Knowledge gained from this study can have potential translational implications for developing new therapeutic strategies for combating ALS.