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

肌萎缩侧索硬化症(ALS)是一种以运动神经元特异性变性为特征的进行性致死性神经退行性疾病。大约20%的家族性肌萎缩侧索硬化症(FALS)病例与超氧化物歧化酶1(SOD1)的特定突变有关。SOD1突变体被认为通过“获得毒性功能”而导致运动神经元死亡。另一方面，由另一个与FALS相关的基因als2编码的alsin被认为是通过功能丧失而导致ALS的，因为als2中与faS相关的突变是隐性遗传的。基于alsin有助于神经保护的假设，我们检验了野生型alsin是否能保护细胞免受SOD1突变体诱导的毒性。我们发现在运动神经元细胞系中，alsin与Fals连锁的SOD1突变体共表达可显著抑制SOD1突变体诱导的细胞死亡。此外，野生型alsin与FALS连锁的SOD1突变体结合，但不与野生型SOD1结合，这表明alsin的神经保护作用与与SOD1突变体形成复合体有关。我们还发现，九个残基的多肽ADNF在体外可以抑制FALS连锁SOD1突变体引起的运动神经元死亡，并改善FALS转基因小鼠的运动能力。

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.