Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene.
Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene.
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DOI：
10.1523/jneurosci.2208-10.2010
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发表时间：
2010-09-08
期刊：
影响因子：
--
通讯作者：
Monani UR
中科院分区：
文献类型：
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作者：
Park GH;Maeno-Hikichi Y;Awano T;Landmesser LT;Monani UR
脊髓性肌萎缩症（SMA）是一种常见的（约1：6400）常染色体隐性遗传神经肌肉疾病，由运动神经元存活蛋白（SMN）缺乏引起。虽然广泛认为缺乏时会导致选择性脊髓运动神经元丢失，但SMA中SMN蛋白的确切细胞作用部位仍不清楚。在这项研究中，我们试图确定选择性耗尽SMN的模型小鼠的运动神经元的后果。消耗但不消除运动神经元祖细胞中的蛋白质会导致SMA样表型。模型小鼠中的神经肌肉无力伴有外周和中枢突触缺陷、神经肌肉接头的电生理异常、肌肉萎缩和运动神经元变性。然而，疾病表型比在表达普遍低水平SMN蛋白的小鼠中观察到的更温和，并且两种症状以及在新生儿中很明显的早期电生理异常以年龄依赖性方式减弱。我们的结论是，选择性敲低运动神经元中的SMN是足够的，但可能不是必要的，以引起疾病的表型，靶向这些细胞将是任何有效的治疗策略的要求。这种认识受到我们的模型小鼠中相对温和的SMA表型的影响，对此的一种解释是非神经元组织中存在正常的SMN水平，其用于调节疾病的严重程度。
Spinal muscular atrophy (SMA) is a common (~1:6400) autosomal recessive neuromuscular disorder caused by a paucity of the Survival of Motor Neuron (SMN) protein. Although widely recognized to cause selective spinal motor neuron loss when deficient, the precise cellular site of action of the SMN protein in SMA remains unclear. In this study we sought to determine the consequences of selectively depleting SMN in the motor neurons of model mice. Depleting but not abolishing the protein in motor neuronal progenitors causes an SMA-like phenotype. Neuromuscular weakness in the model mice is accompanied by peripheral as well as central synaptic defects, electrophysiological abnormalities of the neuromuscular junctions, muscle atrophy and motor neuron degeneration. However, the disease phenotype is more modest than that observed in mice expressing ubiquitously low levels of the SMN protein and both symptoms as well as early electrophysiological abnormalities which are readily apparent in neonates, attenuated in an age dependent manner. We conclude that selective knock-down of SMN in motor neurons is sufficient but may not be necessary to cause a disease phenotype and that targeting these cells will be a requirement of any effective therapeutic strategy. This realization is tempered by the relatively mild SMA phenotype in our model mice, one explanation for which is the presence of normal SMN levels in non-neuronal tissue that serves to modulate disease severity.