Amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Mutant superoxide dismutase 1 (SOD1), as seen in some familial ALS (FALS) cases, is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. Within mitochondria, mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2, affect mitochondrial import by interfering with the translocation machinery (TOM/TIM), and generate toxic free radicals (ROS). Reactive oxygen species (ROS), produced within mitochondria, inhibit the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess increases intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mutant SOD1 can also trigger oxidative reactions , which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Nitration may target neurofilament proteins, affecting axonal transport. Collectively, these mechanisms are predicted to disturb cellular homeostasis, ultimately triggering motor neuron death.

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，简称 ALS）是一种进行性、致命性的神经元退行性疾病。该疾病的特征是大脑和脊髓中运动神经元的特异性死亡，导致随意肌麻痹。在部分家族性肌萎缩侧索硬化症（FALS）病例中，突变型超氧化物歧化酶1（Mutant superoxide dismutase 1，简称 SOD1）不稳定，在运动神经元胞质、轴浆和线粒体中形成聚集体。在线粒体内部，突变型 SOD1 可能干扰抗凋亡蛋白 Bcl-2 的功能，通过干扰转位机制（TOM/TIM）影响线粒体蛋白的输入，并产生有毒的活性氧（Reactive oxygen species，简称 ROS）。在细胞器内部产生的活性氧会抑制 EAAT2 的功能，EAAT2 是主要的胶质谷氨酸转运蛋白，负责大多数突触释放的谷氨酸的再摄取。谷氨酸的过量增加导致细胞内钙离子浓度升高，从而加剧氧化应激和线粒体损伤。突变型 SOD1 还可触发氧化反应，进而通过羟基自由基的形成或蛋白质酪氨酸残基的硝化作用造成损伤。硝化作用可能靶向神经丝蛋白，影响轴突运输。总体而言，这些机制预计将扰乱细胞稳态，最终触发运动神经元死亡。