Elucidation of mechanisms for neuronal death caused by mutant genes in amyotrophic lateral sclerosis

肌萎缩性侧索硬化症（ALS）是一种进行性致死性神经退行性疾病，以运动神经元特异性变性为特征。超氧化物歧化酶1（SOD1）的特异性突变与大约20%的家族性ALS（FALS）病例有关。SOD1突变体被认为通过“毒性功能的获得”导致运动神经元死亡。另一方面，另一个与ALS相关的基因ALS2编码的alsin被认为是通过“功能丧失”导致ALS的原因，因为ALS2中与ALS相关的突变是隐性遗传的。基于alsin有助于神经保护的假设，我们研究了野生型alsin是否能保护细胞免受SOD1突变体诱导的毒性。我们发现alsin与fals相关的SOD1突变体共表达可显著抑制SOD1突变体诱导的运动神经元细胞系细胞死亡。此外，野生型alsin与FALS相关的SOD1突变体结合，但不与野生型SOD1结合，这表明alsin的神经保护作用与SOD1突变体的复合物形成有关。我们还发现，ADNF（一种含有9个残基的多肽）在体外抑制FALS相关SOD1突变体引起的运动神经元死亡，并改善G93A-SOD1转基因小鼠（FALS模型）的运动表现。

Amyotrophic lateral sclerosis(ALS) is a progressive fatal neurodegenerative disease that is characterized with specific degeneration of motor neurons. Specific mutations in superoxide dismutase 1(SOD1) are associated with approximately 20% of familial ALS(FALS) cases. SOD1 mutants are considered to cause motoneuronal death by ‘gain of toxic function'. On the other hand, alsin encoded by another FALS-responsible gene, ALS2, is considered to cause ALS by ‘loss of function', because FALS-linked mutations in ALS2 are recessively inherited. Based on the hypothesis that alsin contributes neuroprotection, we examined whether wild-type alsin protect cells from SOD1 mutants-induced toxicity. We found that co-expression of alsin with FALS-linked SOD1 mutant drastically suppressed SOD1 mutants-induced cell death in motoneuronal cell line. Further, the wild-type alsin binds to FALS- linked SOD1 mutants, but not to wild-type SOD1, suggesting that neuroproptection of alsin correlates with complex formation with SOD1 mutants.We also found that ADNF, a nine-residue polypeptide, suppressed motoneuronal death caused by FALS-linked SOD1 mutants in vitro and improved motor performance of G93A-SOD1 transgenic mice, a model of FALS.