Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Sci Rep. 2017 Oct 24;7(1):13859. doi: 10.1038/s41598-017-14313-z.
Spinal muscular atrophy (SMA) is caused by homozygous mutation of the survival motor neuron 1 (SMN1) gene. Disease severity inversely correlates to the amount of SMN protein produced from the homologous SMN2 gene. We show that SMN protein is naturally released in exosomes from all cell types examined. Fibroblasts from patients or a mouse model of SMA released exosomes containing reduced levels of SMN protein relative to normal controls. Cells overexpressing SMN protein released exosomes with dramatically elevated levels of SMN protein. We observed enhanced quantities of exosomes in the medium from SMN-depleted cells, and in serum from a mouse model of SMA and a patient with Type 3 SMA, suggesting that SMN-depletion causes a deregulation of exosome release or uptake. The quantity of SMN protein contained in the serum-derived exosomes correlated with the genotype of the animal, with progressively less protein in carrier and affected animals compared to wildtype mice. SMN protein was easily detectable in exosomes isolated from human serum, with a reduction in the amount of SMN protein in exosomes from a patient with Type 3 SMA compared to a normal control. Our results suggest that exosome-derived SMN protein may serve as an effective biomarker for SMA.
脊髓性肌萎缩症（SMA）是由生存运动神经元 1（SMN1）基因的纯合突变引起的。疾病的严重程度与从同源 SMN2 基因产生的 SMN 蛋白的量成反比。我们表明 SMN 蛋白是从所有检查过的细胞类型中自然释放到外泌体中的。与正常对照相比，来自 SMA 患者或小鼠模型的成纤维细胞释放的外泌体中 SMN 蛋白水平降低。过表达 SMN 蛋白的细胞释放的外泌体中 SMN 蛋白水平显著升高。我们观察到 SMN 耗尽细胞的培养基中以及 SMA 小鼠模型和 3 型 SMA 患者的血清中外泌体的数量增加，这表明 SMN 耗竭导致外泌体释放或摄取失调。血清来源的外泌体中 SMN 蛋白的含量与动物的基因型相关，与野生型小鼠相比，携带者和受影响动物中的蛋白含量逐渐减少。SMN 蛋白在从人血清中分离的外泌体中很容易检测到，与正常对照相比，3 型 SMA 患者的外泌体中的 SMN 蛋白含量减少。我们的研究结果表明，外泌体衍生的 SMN 蛋白可能作为 SMA 的有效生物标志物。
