Disruption of dystonin in Schwann cells results in late-onset neuropathy and sensory ataxia
Disruption of dystonin in Schwann cells results in late-onset neuropathy and sensory ataxia
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雪旺细胞中肌张力障碍的破坏导致迟发性神经病和感觉共济失调
作者：
Horie M;Yoshioka N;Kusumi S;Sano H;Kurose M;Watanabe-Iida I;Hossain MI;Chiken S;Abe M;Yamamura K;Sakimura K;Nambu A;Shibata M;Takebayashi H
肌张力障碍蛋白（Dstonin，Dst）是肌张力障碍（Dystonia musculorum，dt）小鼠的致病基因，它是一种遗传性疾病，表现为肌张力障碍样运动和共济失调伴感觉变性，在中枢神经系统、外周神经系统（peripheral nervous system，PNS）、肌肉和皮肤等多种组织中表达。然而，表达Dst的细胞类型的表型还没有得到很好的表征。为了解决Dstin Schwann细胞的破坏是否会诱导运动障碍以及它对表型有多大影响的问题，我们使用P0-Cre转基因小鼠和Dst基因诱捕小鼠产生了Dst条件性敲除（cKO）小鼠。首先，我们使用tdTomato报告基因小鼠评估了P0-Cre转基因依赖性Cre重组，然后证实了Schwann细胞中的优先tdTomato表达。在DstcKO小鼠中，雪旺细胞中的DstmRNA表达显著降低，但背根神经节中的大多数感觉神经元中的DstmRNA表达是完整的。接下来，我们分析了DstcKO小鼠的表型。它们在幼年期表现出正常的运动表型，此后开始表现出共济失调。行为学测试和电生理学分析表明DstcKO小鼠的运动能力受损，运动神经传导速度减慢，但这些小鼠没有表现出张力障碍运动。DstcKO小鼠PNS的电子显微镜观察显示显著数量的低髓鞘化轴突和大量浸润的吞噬髓鞘碎片的巨噬细胞。这些结果表明Dst对正常的PNS髓鞘组织是重要的，而Schwann细胞中Dst的破坏可诱导迟发性神经病和感觉性共济失调。要点Dst在Schwann细胞中的破坏可导致迟发性神经病和感觉性共济失调。Dst在周围神经系统中对正常的髓鞘组织是重要的。
Dystonin(Dst) is a causative gene forDystonia musculorum(dt) mice, which is an inherited disorder exhibiting dystonia‐like movement and ataxia with sensory degeneration.Dstis expressed in a variety of tissues, including the central nervous system and the peripheral nervous system (PNS), muscles, and skin. However, theDst‐expressing cell type(s) fordtphenotypes have not been well characterized. To address the questions whether the disruption ofDstin Schwann cells induces movement disorders and how much impact does it have ondtphenotypes, we generatedDstconditional knockout (cKO) mice usingP0‐Cretransgenic mice andDstgene trap mice. First, we assessed theP0‐Cretransgene‐dependent Cre recombination usingtdTomatoreporter mice and then confirmed the preferential tdTomato expression in Schwann cells. In theDstcKO mice,DstmRNA expression was significantly decreased in Schwann cells, but it was intact in most of the sensory neurons in the dorsal root ganglion. Next, we analyzed the phenotype ofDstcKO mice. They exhibited a normal motor phenotype during juvenile periods, and thereafter, started exhibiting an ataxia. Behavioral tests and electrophysiological analyses demonstrated impaired motor abilities and slowed motor nerve conduction velocity inDstcKO mice, but these mice did not manifest dystonic movements. Electron microscopic observation of the PNS ofDstcKO mice revealed significant numbers of hypomyelinated axons and numerous infiltrating macrophages engulfing myelin debris. These results indicate thatDstis important for normal PNS myelin organization andDstdisruption in Schwann cells induces late‐onset neuropathy and sensory ataxia.Main pointsDystonin(Dst) disruption in Schwann cells results in late‐onset neuropathy and sensory ataxia.Dstin Schwann cells is important for normal myelin organization in the peripheral nervous system.