Motor transmission defects with sex differences in a new mouse model of mild spinal muscular atrophy
Motor transmission defects with sex differences in a new mouse model of mild spinal muscular atrophy
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DOI：
10.1016/j.ebiom.2020.102750
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发表时间：
2020-05-01
期刊：
影响因子：
11.1
通讯作者：
Kothary, Rashmi
中科院分区：
文献类型：
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作者：
Deguise, Marc-Olivier;De Repentigny, Yves;Kothary, Rashmi
背景：轻度脊髓性肌萎缩症（SMA）小鼠模型的建立极具挑战性。模型系统的缺乏限制了我们对疾病的较轻形式中的病理生理学事件和衰老过程中SMN耗竭的影响的理解。方法：通过交叉Smn（-/-）; SMN 2和Smn（2B/2B）小鼠产生SMA的轻度小鼠模型，称为Smn（2B/-）; SMN 2（+/-）。这种新的模型的特点是使用行为测试，组织学，蛋白质印迹，肌肉神经电生理学以及超声研究经典的SMA功能和extra-neuronal involvement.Findings：Smn（2B/-）; SMN 2（+/-）小鼠有正常的生存，轻度但持续的运动无力，去神经支配和神经元/神经肌肉接头（NMJ）的传输缺陷，和神经源性肌肉萎缩，是更突出的雄性小鼠。在雌性和雄性小鼠中也发现了位于中央的核增加、内在收缩和松弛肌肉缺陷，其中雄性小鼠占优势。解释：Smn（2B/-）; SMN 2（+/-）小鼠提供了轻度SMA模型，显示出一些标志性特征，包括体重减轻、持续运动无力、电生理传递缺陷、NMJ缺陷和肌肉萎缩。早期和显著增加中央成核和内在电生理缺陷表明肌肉在SMA疾病中发挥的潜在作用。该模型的使用将有助于了解运动神经元和肌肉中最易感的致病分子变化，研究SMN耗竭对衰老的影响，性别差异，最重要的是将为目前接受最近批准的遗传疗法治疗的老龄SMA患者提供指导。(C)2020作者（S）由爱思唯尔公司出版
Background: Mouse models of mild spinal muscular atrophy (SMA) have been extremely challenging to generate. This paucity of model systems has limited our understanding of pathophysiological events in milder forms of the disease and of the effect of SMN depletion during aging.Methods: A mild mouse model of SMA, termed Smn(2B/-);SMN2(+/-), was generated by crossing Smn(-/-);SMN2 and Smn(2B/2B) mice. This new model was characterized using behavioral testing, histology, western blot, muscle-nerve electrophysiology as well as ultrasonography to study classical SMA features and extra-neuronal involvement.Findings: Smn(2B/-);SMN2(+/-) mice have normal survival, mild but sustained motor weakness, denervation and neuronal/neuromuscular junction (NMJ) transmission defects, and neurogenic muscle atrophy that are more prominent in male mice. Increased centrally located nuclei, intrinsic contractile and relaxation muscle defects were also identified in both female and male mice, with some male predominance. There was an absence of extra-neuronal pathology.Interpretation: The Smn(2B/-);SMN2(+/-) mouse provides a model of mild SMA, displaying some hallmark features including reduced weight, sustained motor weakness, electrophysiological transmission deficit, NMJ defects, and muscle atrophy. Early and prominent increase central nucleation and intrinsic electrophysiological deficits demonstrate the potential role played by muscle in SMA disease. The use of this model will allow for the understanding of the most susceptible pathogenic molecular changes in motor neurons and muscles, investigation of the effects of SMN depletion in aging, sex differences and most importantly will provide guidance for the currently aging SMA patients treated with the recently approved genetic therapies. (C) 2020 The Author(s). Published by Elsevier B.V.