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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis
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Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis

机译：基因转移证明肌肉不是家族性肌萎缩性侧索硬化症非细胞自主毒性的主要靶标

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摘要

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive paralysis arising from the premature death of motor neurons. An inherited form is caused by a dominant mutation in the ubiquitously expressed superoxide dismutase (SOD1). SOD1 mutant expression within motor neurons is a determinant of onset and early disease, and mutant accumulation within microglia accelerates disease progression. Muscle also is a likely primary source for toxicity, because retraction of motor axons from synaptic connections to muscle is among the earliest presymptomatic events. To test involvement of muscle in ALS, viral delivery of transcription-mediated siRNA is shown to suppress mutant SOD1 accumulation within muscle alone but to be insufficient to maintain grip strength, whereas delivery to both motor neurons and muscle is sufficient. Use of a deletable mutant gene to diminish mutant SOD1 from muscle did not affect onset or survival. Finally, foilistatin expression encoded by adeno-associated virus chronically inhibited myostatin and produced sustained increases in muscle mass, myofiber number, and fiber diameter, but these increases did not affect survival. Thus, SOD1-mutant-mediated damage within muscles is not a significant contributor to non-cell-autonomous pathogenesis in ALS, and enhancing muscle mass and strength provides no benefit in slowing disease onset or progression.
机译：肌萎缩性侧索硬化症（ALS）是由运动神经元过早死亡引起的致命性进行性麻痹。遗传形式是由普遍表达的超氧化物歧化酶（SOD1）中的显性突变引起的。运动神经元内SOD1突变体的表达是发病和早期疾病的决定因素，小胶质细胞内的突变体积累加速了疾病的进展。肌肉也可能是毒性的主要来源，因为从突触连接到肌肉的运动轴突缩回是最早的症状前事件之一。为了测试肌肉是否参与ALS，转录介导的siRNA的病毒传递可抑制突变型SOD1仅在肌肉中的积累，但不足以保持抓地力，而同时传递至运动神经元和肌肉则足够。使用可删除的突变基因从肌肉中减少突变SOD1不会影响发病或存活。最后，由腺相关病毒编码的箔蛋白抑制素表达长期抑制肌生长抑制素，并导致肌肉质量，肌纤维数量和纤维直径的持续增加，但这些增加并不影响存活率。因此，肌肉内SOD1突变体介导的损伤不是ALS非细胞自主性发病机制的重要贡献，并且增强肌肉质量和强度在减慢疾病发作或进展方面无益处。

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