Treatment with an antibody directed against Nogo-A delays disease progression in the SOD1G93A mouse model of Amyotrophic lateral sclerosis
Treatment with an antibody directed against Nogo-A delays disease progression in the SOD1G93A mouse model of Amyotrophic lateral sclerosis
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DOI：
10.1093/hmg/ddu136
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发表时间：
2014-08-15
影响因子：
3.5
通讯作者：
Greensmith, Linda
中科院分区：
文献类型：
--
作者：
Bros-Facer, Virginie;Krull, David;Greensmith, Linda
肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，脊髓和运动皮层的运动神经元退化。虽然大多数ALS病例是散发的，但10-20%的家族性ALS （fALS）是由Cu-Zn超氧化物歧化酶-1 （SOD1）突变引起的，最近的研究结果表明，C9ORF72基因的六核苷酸重复扩增可能占欧洲fALS病例的30 - 30%。SOD1（G93A）转基因小鼠具有与人ALS相似的表型和病理。在ALS患者和SOD1（G93A）小鼠中，疾病的第一个病理特征表现在神经肌肉连接处，在运动神经元变性之前发生明显的去神经支配。因此，旨在预防或延迟去神经支配的策略可能对ALS有益。在这项研究中，我们发现SOD1（G93A）小鼠肌纤维中Nogo-A水平随着神经肌肉功能障碍标志物（CHRNA1/MUSK）的升高而升高。从70日龄开始，用抗nogo - a抗体（GSK577548）对症治疗SOD1（G93A）小鼠，在90天（疾病症状晚期）显著改善后肢肌肉神经支配，导致肌肉力量和运动单位存活增加，运动神经元存活显著增加。然而，抗nogo - a抗体治疗的SOD1（G93A）小鼠在终末期疾病中并不是所有方面都能保持这种改善。这些结果表明，抗Nogo-A抗体治疗可显著改善SOD1(G93A) ALS小鼠模型的神经肌肉功能，至少在疾病的早期阶段是如此，并提示药物抑制Nogo-A可能是ALS的一种疾病改善方法。
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder in which motor neurons in the spinal cord and motor cortex degenerate. Although the majority of ALS cases are sporadic, mutations in Cu-Zn superoxide dismutase-1 (SOD1) are causative for 10-20% of familial ALS (fALS), and recent findings show that a hexanucleotide repeat expansion in the C9ORF72 gene may account for > 30% of fALS cases in Europe. SOD1(G93A) transgenic mice have a phenotype and pathology similar to human ALS. In both ALS patients and SOD1(G93A) mice, the first pathological features of disease manifest at the neuromuscular junction, where significant denervation occurs prior to motor neuron degeneration. Strategies aimed at preventing or delaying denervation may therefore be of benefit in ALS. In this study, we show that Nogo-A levels increase in muscle fibres of SOD1(G93A) mice along with the elevation of markers of neuromuscular dysfunction (CHRNA1/MUSK). Symptomatic treatment of SOD1(G93A) mice from 70 days of age with an anti-Nogo-A antibody (GSK577548) significantly improves hindlimb muscle innervation at 90 days, a late symptomatic stage of disease, resulting in increased muscle force and motor unit survival and a significant increase in motor neuron survival. However, not all aspects of this improvement in anti-Nogo-A antibody-treated SOD1(G93A) mice were maintained at end-stage disease. These results show that treatment with anti-Nogo-A antibody significantly improves neuromuscular function in the SOD1(G93A) mouse model of ALS, at least during the earlier stages of disease and suggest that pharmacological inhibition of Nogo-A may be a disease-modifying approach in ALS.