Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.
Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.
Mol Cell Neurosci. 2018 Oct;92:12-16. doi: 10.1016/j.mcn.2018.06.002. Epub 2018 Jun 18.
Dominant mutations in an antioxidant enzyme superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease characterized by loss of motor neurons. Oxidative stress has also been linked to many of the neurodegenerative diseases and is likely a central mechanism of motor neuron death in ALS. Astrocytes derived from mutant SOD1 mouse models or patients play a significant role in the degeneration of spinal motor neurons in ALS through a non-cell-autonomous process. Here we characterize the neuroprotective effects and mechanisms of urate (a.k.a. uric acid), a major endogenous antioxidant and a biomarker of favorable ALS progression rates, in a cellular model of ALS. Our results demonstrate a significant protective effect of urate against motor neuron injury evoked by mutant astrocytes derived from SOD1 mice or hydrogen peroxide induced oxidative stress. Overall, these results implicate astrocyte dependent protective effect of urate in a cellular model of ALS. These findings together with our biomarker data may advance novel targets for treating motor neuron disease.
抗氧化酶超氧化物歧化酶-1（SOD1）的显性突变导致肌萎缩侧索硬化症（ALS），这是一种成年起病的神经退行性疾病，其特征是运动神经元丧失。氧化应激也与许多神经退行性疾病有关，并且可能是 ALS 中运动神经元死亡的核心机制。源自突变 SOD1 小鼠模型或患者的星形胶质细胞通过非细胞自主过程在 ALS 中脊髓运动神经元的退化中发挥重要作用。在这里，我们在 ALS 的细胞模型中描述了尿酸（也称为尿酸）的神经保护作用及其机制，尿酸是一种主要的内源性抗氧化剂和 ALS 进展率良好的生物标志物。我们的结果表明尿酸对源自 SOD1 小鼠的突变星形胶质细胞或过氧化氢诱导的氧化应激引起的运动神经元损伤具有显著的保护作用。总体而言，这些结果表明尿酸在 ALS 的细胞模型中具有星形胶质细胞依赖性的保护作用。这些发现以及我们的生物标志物数据可能为治疗运动神经元疾病提供新的靶点。
