Tradewell Miranda L, Durham Heather D
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Neuroreport. 2010 Oct 27;21(15):976-9. doi: 10.1097/WNR.0b013e32833ddd45.
Amyotrophic lateral sclerosis (ALS) is an adult-onset, rapidly progressing, fatal disease occurring in both familial and sporadic forms. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) cause ALS through a gain of toxic function. Calpain activity is increased in mutant SOD1 (SOD1(G93A)) transgenic mice and in models of ischemia because of increased cytosolic calcium, which has been documented in motor neurons in rodent models of familial ALS and in sporadic ALS patients. We report that inhibition of calpain activity using calpastatin prevented the toxicity of SOD1(G93A) in motor neurons of dissociated spinal cord cultures, prolonging viability of and reducing the proportion containing SOD1(G93A) inclusions. The data support the central role of calcium dysregulation in ALS and identify a potential therapeutic pathway.
肌萎缩侧索硬化症（ALS）是一种成年起病、进展迅速的致命疾病，有家族性和散发性两种形式。编码铜/锌超氧化物歧化酶（SOD1）的基因突变通过获得毒性功能导致ALS。由于胞质钙增加，在突变型SOD1（SOD1(G93A)）转基因小鼠和缺血模型中钙蛋白酶活性增加，这在家族性ALS的啮齿动物模型的运动神经元和散发性ALS患者中已得到证实。我们报告称，使用钙蛋白酶抑制蛋白抑制钙蛋白酶活性可预防SOD1(G93A)在解离脊髓培养物的运动神经元中的毒性，延长其存活能力并减少含有SOD1(G93A)包涵体的比例。这些数据支持钙调节异常在ALS中的核心作用，并确定了一条潜在的治疗途径。
