Urushitani Makoto
Neurogene Unit, Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
Brain Nerve. 2008 Jun;60(6):643-51.
Recent progress in clinical genetics has explored various mutations or associated genes in both familial and sporadic amyotrophic lateral sclerosis (ALS). Mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS, and mutant SOD1 transgenic mice are still regarded as the best ALS model animals for the first step of therapeutic estimation. Emerging evidence indicates that SOD1 is secreted in spite of lacking translocation signal. We previously found chromogranins interact with ALS-linked SOD1 mutants, but not with wild-type, and promote the secretion SOD1 mutants. Moreover, extracellular SOD1 mutant activates microglia and kills motor neuron. This scenario may well explain non-cell-autonomous fashion of mutant SOD1-induced pathology in ALS. Accordingly, vaccination targeting extracellular SOD1 mutants significantly delays disease onset and prolongs lifespan of mutant SOD1 transgenic mice. Moreover, intraventricular application of ant-mutant SOD1 antibody also showed beneficial effect. In this review, the rationale between protein misfolding of mutant SOD1 and effect of immunization is delineated and further perspective of this non-invasive treatment not only for mutant SOD1 but also for sporadic ALS is discussed.
临床遗传学的最新进展探究了家族性和散发性肌萎缩侧索硬化症（ALS）中的各种突变或相关基因。超氧化物歧化酶1（SOD1）突变占家族性ALS的20%，突变型SOD1转基因小鼠仍被视为治疗评估第一步的最佳ALS模型动物。新出现的证据表明，尽管缺乏转运信号，SOD1仍会分泌。我们之前发现嗜铬粒蛋白与ALS相关的SOD1突变体相互作用，但不与野生型相互作用，并促进SOD1突变体的分泌。此外，细胞外SOD1突变体激活小胶质细胞并杀死运动神经元。这种情况很可能解释了突变型SOD1在ALS中诱导病理的非细胞自主方式。因此，针对细胞外SOD1突变体的疫苗接种显著延迟了疾病发作并延长了突变型SOD1转基因小鼠的寿命。此外，脑室内应用抗突变型SOD1抗体也显示出有益效果。在这篇综述中，阐述了突变型SOD1蛋白质错误折叠与免疫效果之间的基本原理，并讨论了这种非侵入性治疗不仅针对突变型SOD1，也针对散发性ALS的进一步前景。
