Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment.
Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment.
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DOI：
10.1371/journal.pone.0155032
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Sintusek P;Catapano F;Angkathunkayul N;Marrosu E;Parson SH;Morgan JE;Muntoni F;Zhou H
胃肠道（GI）缺陷，包括胃食管反流、便秘和胃排空延迟，在脊髓性肌萎缩症（SMA）患者中很常见。在运动神经元存活（SMN）蛋白缺乏的小鼠模型中也发现了类似的GI运动障碍。我们先前描述了SMA小鼠骨骼肌和脊髓中的血管缺陷，我们假设在这些小鼠中观察到的GI病理学可能涉及类似的缺陷。因此，我们研究了严重SMA小鼠模型中小肠的大体解剖结构、肠血管系统和神经元。我们还评估了胃肠道组织病理学的治疗反应，全身管理的吗啉代反义寡核苷酸（AON）的设计，以增加SMN蛋白的表达。在SMA小鼠的小肠中检测到显著的解剖学和组织病理学异常，血管密度显著降低，肠神经元过多和巨噬细胞浸润增加。在新生小鼠中进行全身AON治疗后，观察到的所有异常均显著恢复至接近正常水平。我们得出结论，在这些SMA小鼠中观察到的GI组织病理学表型和功能缺陷与SMN缺陷密切相关，可以通过全身给予AON来挽救SMN缺陷。这项关于重度SMA小鼠胃肠道系统组织病理学变化的研究进一步表明了SMN在多个组织中发挥的复杂作用，并表明至少在SMA小鼠中，外周组织中SMN产生的恢复对于最佳结局至关重要。
Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.