A critical smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology
A critical smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology
复制标题
DOI：
10.1016/j.nmd.2011.09.007
复制
发表时间：
2012-03-01
影响因子：
2.8
通讯作者：
Kothary, Rashmi
中科院分区：
文献类型：
--
作者：
Bowerman, Melissa;Murray, Lyndsay M.;Kothary, Rashmi
脊髓性肌萎缩症（SMA）是由SMN1基因的突变/缺失引起的，其特征是下部运动神经元的丧失和骨骼肌萎缩。SMA在临床上是异质性的，疾病从严重到轻度不等。在这里，我们确定了在中间Smn（2B/-）小鼠模型中决定SMA发病的Smn的临界阈值。Smn（2/B-）蛋白在正常水平约15%时，Smn（2/B-）小鼠出现体重减轻、运动神经元丢失和运动缺陷。重要的是，这些小鼠在P10之前都是无表型的，平均预期寿命为28天。他们表现出神经肌肉连接（NMJ）病理与肌肉间差异易感性和突触前和突触后缺陷之间的关联。我们的研究表明，由于Smn（2B/2B）小鼠在表型上是正常的，因此仅最低限度地增加Smn蛋白水平就可能有显著的益处。此外，重度和中度SMA小鼠模型的NMJ病理变化表明，未来的治疗方法应适应SMA的严重程度。爱思唯尔B.V.版权所有
Spinal muscular atrophy (SMA) is caused by mutations/deletions within the SMN1 gene and characterized by loss of lower motor neurons and skeletal muscle atrophy. SMA is clinically heterogeneous, with disease ranging from severe to mild. Here, we identify a critical threshold of Smn that dictates onset of SMA in the intermediate Smn(2B/-) mouse model. With about 15% normal level of Smn protein, Smn(2/B-) mice display reduced body weight, motor neuron loss and motor defects. Importantly, these mice are phenotype-free until P10 with a median life expectancy of 28 days. They show neuromuscular junction (NMJ) pathology with an inter-muscular differential vulnerability and an association between pre- and post-synaptic defects. Our work suggests that increasing Smn protein levels only minimally could be of significant benefit since Smn(2B/2B) mice are phenotypically normal. Further, the finding that NMJ pathology varies between severe and intermediate SMA mouse models, suggests that future therapies be adapted to the severity of SMA. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.