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Mislocalization of SMN from the I-band and M-band in human skeletal myofibers in spinal muscular atrophy associates with primary structural alterations of the sarcomere
Cell and Tissue Research ( IF 3.6 ) Pub Date : 2020-07-16 , DOI: 10.1007/s00441-020-03236-3
María T Berciano 1, 2 , María S Castillo-Iglesias 3 , J Fernando Val-Bernal 4 , Vanesa Lafarga 5 , José C Rodriguez-Rey 1 , Miguel Lafarga 2, 3 , Olga Tapia 2, 6
Affiliation  

Spinal muscular atrophy (SMA) is caused by a deletion or mutation of the survival motor neuron 1 (SMN1) gene. Reduced SMN levels lead to motor neuron degeneration and muscular atrophy. SMN protein localizes to the cytoplasm and Cajal bodies. Moreover, in myofibrils from Drosophila and mice, SMN is a sarcomeric protein localized to the Z-disc. Although SMN participates in multiple functions, including the biogenesis of spliceosomal small nuclear ribonucleoproteins, its role in the sarcomere is unclear. Here, we analyzed the sarcomeric organization of SMN in human control and type I SMA skeletal myofibers. In control sarcomeres, we demonstrate that human SMN is localized to the titin-positive M-band and actin-positive I-band, and to SMN-positive granules that flanked the Z-discs. Co-immunoprecipitation assays revealed that SMN interacts with the sarcomeric protein actin, α-actinin, titin, and profilin2. In the type I SMA muscle, SMN levels were reduced, and atrophic (denervated) and hypertrophic (nondenervated) myofibers coexisted. The hypertrophied myofibers, which are potential primary targets of SMN deficiency, exhibited sites of focal or segmental alterations of the actin cytoskeleton, where the SMN immunostaining pattern was altered. Moreover, SMN was relocalized to the Z-disc in overcontracted minisarcomeres from hypertrophic myofibers. We propose that SMN could have an integrating role in the molecular components of the sarcomere. Consequently, low SMN levels might impact the normal sarcomeric architecture, resulting in the disruption of myofibrils found in SMA muscle. This primary effect might be independent of the neurogenic myopathy produced by denervation and contribute to pathophysiology of the SMA myopathy.

中文翻译:

脊髓性肌萎缩症中人类骨骼肌纤维中 I 带和 M 带 SMN 的错误定位与肌节的主要结构改变有关

脊髓性肌萎缩症 (SMA) 是由运动神经元存活 1 (SMN1) 基因的缺失或突变引起的。SMN 水平降低会导致运动神经元变性和肌肉萎缩。SMN 蛋白定位于细胞质和 Cajal 小体。此外,在来自果蝇和小鼠的肌原纤维中,SMN 是一种定位于 Z 盘的肌节蛋白。尽管 SMN 参与多种功能,包括剪接体小核核糖核蛋白的生物发生,但其在肌节中的作用尚不清楚。在这里,我们分析了人类控制和 I 型 SMA 骨骼肌纤维中 SMN 的肌节组织。在对照肌节中,我们证明人类 SMN 位于肌动蛋白阳性 M 带和肌动蛋白阳性 I 带,以及位于 Z 盘两侧的 SMN 阳性颗粒。共免疫沉淀分析显示 SMN 与肌节蛋白肌动蛋白、α-肌动蛋白、肌联蛋白和 profilin2 相互作用。在 I 型 SMA 肌肉中,SMN 水平降低,并且萎缩(去神经支配)和肥大(非去神经支配)肌纤维共存。肥大的肌纤维是 SMN 缺陷的潜在主要目标,显示出肌动蛋白细胞骨架的局灶性或节段性改变,其中 SMN 免疫染色模式发生了改变。此外,SMN 被重新定位到来自肥大肌纤维的过度收缩的小肌节中的 Z 盘。我们建议 SMN 可以在肌节的分子成分中发挥整合作用。因此,低 SMN 水平可能会影响正常的肌节结构,导致 SMA 肌肉中发现的肌原纤维的破坏。
更新日期:2020-07-16
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