Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder that results in death due to respiratory failure. Many genetic defects are associated with ALS; one such defect is a mutation in the gene encoding optineurin (OPTN). Using an optineurin null mouse (Optn^-/-), we sought to characterize the impact of optineurin deficiency on respiratory neurodegeneration. Respiratory function was assessed at 6 and 12 mo of age using whole body plethysmography at baseline during normoxia (FiO₂: 0.21; N₂ balance) and during a respiratory challenge with hypoxia and hypercapnia (FiCO₂: 0.07, FiO₂: 0.10; N₂ balance). Histological analyses to assess motor neuron viability and respiratory nerve integrity were performed in the medulla, cervical spinal cord, hypoglossal nerve, and phrenic nerve. Minute ventilation, peak inspiratory flow, and peak expiratory flow are significantly reduced during a respiratory challenge in 6 mo Optn^-/-mice. By 12 mo, tidal volume is also significantly reduced in Optn^-/- mice. Furthermore, 12mo Optn^-/- mice exhibit hypoglossal motor neuron loss, phrenic and hypoglossal dysmyelination, and accumulated mitochondria in the hypoglossal nerve axons. Overall, these data indicate that Optn^-/- mice display neurodegenerative respiratory dysfunction and are a useful model to study the impact of novel therapies on respiratory function for optineurin-deficient ALS patients.

肌萎缩侧索硬化 (ALS) 是一种破坏性的神经退行性疾病，可导致呼吸衰竭而死亡。许多遗传缺陷与 ALS 相关。一种这样的缺陷是编码视神经调节蛋白 ( OPTN )的基因发生突变。使用视神经调节蛋白无效小鼠 ( Optn ^-/- )，我们试图表征视神经调节蛋白缺乏对呼吸神经变性的影响。在正常氧（FiO ₂：0.21；N ₂平衡）和低氧和高碳酸血症的呼吸挑战期间（FiCO ₂：0.07，FiO ₂：0.10；N ₂平衡）。在延髓、颈脊髓、舌下神经和膈神经中进行了评估运动神经元活力和呼吸神经完整性的组织学分析。在 6 个月Optn ^-/-小鼠的呼吸挑战期间，分钟通气量、峰值吸气流量和峰值呼气流量显着降低。到 12 个月时，Optn ^-/-小鼠的潮气量也显着降低。此外，12mo Optn ^-/-小鼠表现出舌下运动神经元丢失、膈和舌下髓鞘形成障碍，以及在舌下神经轴突中积累线粒体。总体而言，这些数据表明Optn ^-/- 小鼠表现出神经退行性呼吸功能障碍，是研究新型疗法对视神经调节蛋白缺陷型 ALS 患者呼吸功能影响的有用模型。