Nagano Isao, Murakami Tetsuro, Manabe Yasuhiro, Abe Koji
Department of Neurology, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, 700-8558, Okayama, Japan.
Life Sci. 2002 Dec 20;72(4-5):541-8. doi: 10.1016/s0024-3205(02)02249-x.
The primary pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS) have been elusive. Some of the mechanisms would be implicated in an imbalance between death and survival factors, and impairment of DNA repair possibly caused by oxidative stress. Phosphatidylinositol 3-kinase (PI3-K) and its downstream effector, Akt/protein kinase B (PKB), have been shown to play a pivotal role in neuronal survival against apoptosis supported by neurotrophic factors. To elucidate the mechanisms of motor neuron death in ALS, we examined the expression of PI3-K, Akt, and the DNA repair enzyme redox factor-1 (Ref-1) protein in the spinal cord of transgenic mice with an ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) gene, a valuable model for human ALS. Immunoblotting and immunocytochemical analyses showed that most spinal motor neurons lost immunoreactivity for PI3-K, Akt, and Ref-1 in the presymptomatic stage that preceded a significant loss of neurons. These results suggest that an early decrease of survival signal proteins and a DNA repair enzyme in the spinal motor neurons may account for the mutant SOD1-mediated motor neuron death in this animal model of ALS.
肌萎缩侧索硬化症（ALS）的主要发病机制一直难以捉摸。其中一些机制可能与死亡和生存因子之间的失衡以及可能由氧化应激导致的DNA修复受损有关。磷脂酰肌醇3激酶（PI3-K）及其下游效应物Akt/蛋白激酶B（PKB）已被证明在神经营养因子支持的神经元抗凋亡存活中起关键作用。为了阐明ALS中运动神经元死亡的机制，我们检测了携带与ALS相关的突变型铜/锌超氧化物歧化酶（SOD1）基因的转基因小鼠脊髓中PI3-K、Akt和DNA修复酶氧化还原因子-1（Ref-1）蛋白的表达，该转基因小鼠是人类ALS的一个有价值的模型。免疫印迹和免疫细胞化学分析表明，在神经元显著丢失之前的症状前期，大多数脊髓运动神经元对PI3-K、Akt和Ref-1失去免疫反应性。这些结果表明，在这个ALS动物模型中，脊髓运动神经元中存活信号蛋白和DNA修复酶的早期减少可能是突变型SOD1介导的运动神经元死亡的原因。
