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. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2447 CPTAC Assay Portal]

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）是一种进行性、致命性的运动神经元退行性病变。此病症的特征为大脑和脊髓中运动神经元的特异性死亡，进而导致随意肌的麻痹。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, SOD1）不稳定，在运动神经元细胞质、轴突浆和线粒体中形成聚集。在线粒体中，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（转位器/转运器，TOM/TIM）影响线粒体蛋白的导入，并产生有毒的活性氧自由基（Reactive oxygen species, ROS）。线粒体内部产生的活性氧物种（ROS）会抑制主要胶质谷氨酸转运蛋白（EAAT2）的功能，该蛋白负责大部分突触释放的谷氨酸的再摄取。谷氨酸的过量增加细胞内钙离子浓度，进而增强氧化应激和线粒体损伤。突变型SOD1还能引发氧化反应，通过形成羟基自由基或蛋白质酪氨酸残基硝化作用导致损伤。硝化作用可能靶向神经丝蛋白，影响轴突运输。综合这些机制，预计将扰乱细胞稳态，最终触发运动神经元死亡。与此通路相关的蛋白质可通过[https://assays.cancer.gov/available_assays?wp_id=WP2447 CPTAC检测门户]进行针对性的检测。