Spinal muscular atrophy is (SMA) is a devastating, autosomal recessive neuromuscular disease resulting in muscle atrophy, neurodegeneration, and is the leading genetic cause of infant death. SMA arises when there are homozygous deletion mutations in the human SMN1 gene, leading to a decrease in corresponding SMN1 protein. Although SMN1 is expressed across multiple tissue types, much of the previous research into SMA focused on the neuronal aspect of the disease, overlooking many of the potential non-neuronal aspects of the disease. Therefore, we sought to address this gap in knowledge by modeling SMA in the nematode Caenorhabditis elegans We used a previously uncharacterized allele which resulted in the onset of mild SMA-like phenotypes allowing us to monitor the onset of phenotypes at different stages. We observed that these mutant animals recapitulated many key features of the human disease, and most importantly, we observed that muscle dysfunction precedes neurodegeneration. Furthermore, we tested the therapeutic efficacy of targeting endoplasmic reticulum (ER) stress in non-neuronal cells and found it to be more effective than targeting ER stress in neuronal cells. We also found that the most potent therapeutic potential came from a combination of ER- and neuromuscular junction (NMJ)-targeting drugs. Together, our results suggest an important non-neuronal component of SMA pathology and highlight new considerations for therapeutic intervention.

中文翻译：

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调节内质网应激反应可减轻脊髓性肌萎缩的秀丽隐杆线虫模型中的神经变性。

脊髓性肌萎缩症 (SMA) 是一种破坏性的常染色体隐性神经肌肉疾病，可导致肌肉萎缩、神经变性，并且是导致婴儿死亡的主要遗传原因。当人SMN1基因中存在纯合缺失突变，导致相应 SMN1 蛋白减少时，就会出现 SMA 。尽管 SMN1 在多种组织类型中表达，但之前对 SMA 的大部分研究都集中在该疾病的神经元方面，而忽略了该疾病的许多潜在的非神经元方面。因此，我们试图通过对线虫秀丽隐杆线虫中的SMA 进行建模来解决这一知识差距我们使用了先前未表征的等位基因，该等位基因导致轻度 SMA 样表型的出现，使我们能够监测不同阶段表型的出现。我们观察到这些突变动物重现了人类疾病的许多关键特征，最重要的是，我们观察到肌肉功能障碍先于神经变性。此外，我们测试了靶向非神经元细胞中的内质网 (ER) 应激的治疗效果，发现它比靶向神经元细胞中的 ER 应激更有效。我们还发现，最有效的治疗潜力来自 ER 和神经肌肉接头 (NMJ) 靶向药物的组合。总之，我们的结果表明 SMA 病理学的一个重要的非神经元成分，并突出了治疗干预的新考虑。