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首页> 外文期刊>The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation >Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models
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Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models

机译：肌肉特异性 SMN 减少揭示了脊髓性肌萎缩症模型中的运动神经元非依赖性疾病

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摘要

Paucity of the survival motor neuron (SMN) protein triggers the oft-fatal infantile-onset motor neuron disorder, spinal muscular atrophy (SMA). Augmenting the protein is one means of treating SMA and recently led to FDA approval of an intrathecally delivered SMN-enhancing oligonucleotide currently in use. Notwithstanding the advent of this and other therapies for SMA, it is unclear whether the paralysis associated with the disease derives solely from dysfunctional motor neurons that may be efficiently targeted by restricted delivery of SMN-enhancing agents to the nervous system, or stems from broader defects of the motor unit, arguing for systemic SMN repletion. We investigated the disease-contributing effects of low SMN in one relevant peripheral organ - skeletal muscle - by selectively depleting the protein in only this tissue. We found that muscle deprived of SMN was profoundly damaged. Although a disease phenotype was not immediately obvious, persistent low levels of the protein eventually resulted in muscle fiber defects, neuromuscular junction abnormalities, compromised motor performance, and premature death. Importantly, restoring SMN after the onset of muscle pathology reversed disease. Our results provide the most compelling evidence yet for a direct contributing role of muscle in SMA and argue that an optimal therapy for the disease must be designed to treat this aspect of the dysfunctional motor unit.
机译：存活运动神经元 （SMN） 蛋白的缺乏会引发经常致命的婴儿发病运动神经元疾病，即脊髓性肌萎缩症 （SMA）。增强蛋白质是治疗SMA的一种方法，最近导致FDA批准了目前正在使用的鞘内递送SMN增强寡核苷酸。尽管这种疗法和其他疗法已经出现，但目前尚不清楚与该疾病相关的瘫痪是否仅源于功能失调的运动神经元，这些神经元可能通过限制向神经系统的 SMN 增强剂递送来有效靶向，或者源于更广泛的运动单元缺陷，主张全身性 SMN 补充。我们通过选择性地消耗该组织中的蛋白质，研究了低SMN在一个相关外周器官（骨骼肌）中的疾病促成作用。我们发现，被剥夺SMN的肌肉受到严重损害。虽然疾病表型并不明显，但持续的低水平蛋白质最终导致肌纤维缺陷、神经肌肉接头异常、运动性能受损和过早死亡。重要的是，在肌肉病变发作后恢复SMN可以逆转疾病。我们的研究结果为肌肉在SMA中的直接作用提供了最令人信服的证据，并认为必须设计该疾病的最佳疗法来治疗功能失调的运动单位的这一方面。

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