SARM1 knockout does not rescue neuromuscular phenotypes in a Charcot-Marie-Tooth disease Type 1A mouse model.
SARM1 knockout does not rescue neuromuscular phenotypes in a Charcot-Marie-Tooth disease Type 1A mouse model.
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DOI：
10.1111/jns.12483
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Höke A
中科院分区：
文献类型：
--
作者：
Moss KR;Johnson AE;Bopp TS;Yu AT;Perry K;Chung T;Höke A
Charcot-Marie-Tooth病1A型（CMT1A）是由PMP22基因的重复引起的，是最常见的遗传性周围神经病变。尽管CMT1A是一种髓鞘异常周围神经病变，继发性轴突变性已被认为驱动患者的功能缺陷。鉴于SARM1敲除是程序性轴突退化途径的有效抑制剂，我们询问SARM1敲除是否可以挽救CMT1A模型（C3-PMP）小鼠的神经肌肉表型。将CMT1A小鼠与SARM1敲除小鼠杂交，生成CMT1A/SARM1−/−小鼠。采用一系列行为测试来评估运动和感觉运动功能。对坐骨神经胫骨支进行电生理和组织学研究。此外，还对腓肠肌和比目鱼肌形态进行了组织学评价。尽管在CMT1A模型小鼠中观察到明显的行为和电生理缺陷，但敲除SARM1并没有显著改善。神经形态测量显示，CMT1A模型小鼠主要存在髓磷脂缺陷，而SARM1敲除对所有神经形态测量均无改善。同样，敲除SARM1也不能改善CMT1A模型小鼠的肌肉形态测定缺陷。我们的研究结果表明，程序性轴突退化途径抑制对CMT1A模型小鼠没有治疗效果。我们的研究结果表明，在CMT1A小鼠中观察到的临床表型可能主要是由长时间的髓鞘发育异常引起的，这激发了对这些小鼠髓鞘发育异常机制的进一步研究，并有必要开发改进的CMT1A啮齿动物模型，以概括患者观察到的继发性轴突变性。
Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice. CMT1A mice were bred with SARM1 knockout mice to generate CMT1A/SARM1 −/− mice. A series of behavioral assays were employed to evaluate motor and sensorimotor function. Electrophysiological and histological studies of the tibial branch of the sciatic nerve were performed. Additionally, gastrocnemius and soleus muscle morphology were also evaluated histologically. Although clear behavioral and electrophysiological deficits were observed in CMT1A model mice, SARM1 knockout conferred no significant improvement. Nerve morphometry revealed predominantly myelin deficits in CMT1A model mice and SARM1 knockout yielded no improvement in all nerve morphometry measures. Similarly, muscle morphometry deficits in CMT1A model mice were not improved by SARM1 knockout. Our findings demonstrate that programmed axon degeneration pathway inhibition does not provide therapeutic benefit in CMT1A model mice. Our results indicate that the clinical phenotypes observed in CMT1A mice are likely caused primarily by prolonged dysmyelination, motivate further investigation into mechanisms of dysmyelination in these mice and necessitate the development of improved CMT1A rodent models that recapitulate the secondary axon degeneration observed in patients.
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影响因子：
4.7
作者：
Cheng HC;Burke RE
通讯作者：
Burke RE
DOI：
10.1038/s41583-020-0269-3
发表时间：
2020-04
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Coleman MP;Höke A
通讯作者：
Höke A
影响因子：
6.1
作者：
Horste, Gerd Meyer Zu;Miesbach, Timo A.;Sereda, Michael W.
通讯作者：
Sereda, Michael W.
影响因子：
2.5
作者：
Moss KR;Bopp TS;Johnson AE;Höke A
通讯作者：
Höke A
影响因子：
9.2
作者：
Ferri, A;Sanes, JR;Kato, AC
通讯作者：
Kato, AC