| Autor: |
Berciano MT; Departamento de Biología Molecular, Universidad de Cantabria-IDIVAL, Santander, Spain.; Instituto de Investigación Sanitaria Valdecilla (IDIVAL) and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain., Castillo-Iglesias MS; Departamento de Anatomía y Biología Celular, Universidad de Cantabria-IDIVAL, Santander, Spain., Val-Bernal JF; Unidad de Patología, Departamento de Ciencias Médicas y Quirúrgicas, Universidad de Cantabria-IDIVAL, Santander, Spain., Lafarga V; Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain., Rodriguez-Rey JC; Departamento de Biología Molecular, Universidad de Cantabria-IDIVAL, Santander, Spain., Lafarga M; Instituto de Investigación Sanitaria Valdecilla (IDIVAL) and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain. lafargam@unican.es.; Departamento de Anatomía y Biología Celular, Universidad de Cantabria-IDIVAL, Santander, Spain. lafargam@unican.es., Tapia O; Instituto de Investigación Sanitaria Valdecilla (IDIVAL) and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain. otapia@idival.org.; Universidad Europea del Atlántico, Santander, Spain. otapia@idival.org. |
| Abstrakt: |
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. |
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