Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons.
Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons.
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DOI：
10.1371/journal.pone.0075866
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rimer M
中科院分区：
文献类型：
--
作者：
Paez-Colasante X;Seaberg B;Martinez TL;Kong L;Sumner CJ;Rimer M
在遗传性儿童神经肌肉疾病脊肌萎缩症(SMA)中，运动神经元的低死亡和严重的肌肉无力是由于运动神经元(SMN)普遍表达的蛋白存活减少所致。尽管SMA小鼠概括了人类疾病的许多特征，但尚不清楚它们的寿命短和运动无力是否主要是由于运动神经元的细胞自主缺陷。以Hb9Cre为驱动力，选择性上调条件性SMAΔ7小鼠运动神经元中SMN的表达。与先前在同一小鼠上使用胆碱乙酰转移酶(ChATCre+)作为驱动因素的研究以及在另一种条件SMA小鼠上使用Hb9Cre作为驱动因素的另一项报告不同，我们发现在存活、体重、运动行为和突触前神经丝积累方面没有改善。然而，像在ChATCre+小鼠中一样，我们检测到终板大小的挽救和神经肌肉接头(NMJ)失神经状态的缓解。终板大小的挽救发生在肌纤维大小没有增加的情况下，这表明终板大小是由这些动物的运动神经元决定的。实时荧光定量聚合酶链式反应显示，与ChATCre+SMA小鼠相比，Hb9Cre+SMA小鼠脊髓SMN转录本的表达显著降低。这表明我们缺乏整体的表型改善，很可能是由于Hb9Cre驱动的重组效率出人意料地低。尽管如此，低水平的SMN足以挽救两个NMJ结构参数，表明这些运动神经元细胞的自主表型对运动神经元SMN水平的变化非常敏感。我们的结果直接表明，即使是那些在提高运动神经元SMN方面效果非常轻微的治疗干预措施，也可能缓解SMA患者的神经肌肉表型。
In the inherited childhood neuromuscular disease spinal muscular atrophy (SMA), lower motor neuron death and severe muscle weakness result from the reduction of the ubiquitously expressed protein survival of motor neuron (SMN). Although SMA mice recapitulate many features of the human disease, it has remained unclear if their short lifespan and motor weakness are primarily due to cell-autonomous defects in motor neurons. Using Hb9Cre as a driver, we selectively raised SMN expression in motor neurons in conditional SMAΔ7 mice. Unlike a previous study that used choline acetyltransferase (ChATCre+) as a driver on the same mice, and another report that used Hb9Cre as a driver on a different line of conditional SMA mice, we found no improvement in survival, weight, motor behavior and presynaptic neurofilament accumulation. However, like in ChATCre+ mice, we detected rescue of endplate size and mitigation of neuromuscular junction (NMJ) denervation status. The rescue of endplate size occurred in the absence of an increase in myofiber size, suggesting endplate size is determined by the motor neuron in these animals. Real time-PCR showed that the expression of spinal cord SMN transcript was sharply reduced in Hb9Cre+ SMA mice relative to ChATCre+ SMA mice. This suggests that our lack of overall phenotypic improvement is most likely due to an unexpectedly poor recombination efficiency driven by Hb9Cre. Nonetheless, the low levels of SMN were sufficient to rescue two NMJ structural parameters indicating that these motor neuron cell autonomous phenotypes are very sensitive to changes in motoneuronal SMN levels. Our results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients.
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DOI：
10.1523/jneurosci.2208-10.2010
发表时间：
2010-09-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Park GH;Maeno-Hikichi Y;Awano T;Landmesser LT;Monani UR
通讯作者：
Monani UR
影响因子：
3.7
作者：
Hammond SM;Gogliotti RG;Rao V;Beauvais A;Kothary R;DiDonato CJ
通讯作者：
DiDonato CJ
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
14.9
作者：
Oberdoerffer, P;Otipoby, KL;Rajewsky, K
通讯作者：
Rajewsky, K
影响因子：
15.9
作者：
Avila, Amy M.;Burnett, Barrington G.;Sumner, Charlotte J.
通讯作者：
Sumner, Charlotte J.