Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.

译文

:2D型夏洛特-玛丽牙齿疾病(CMT2D)是一种外周神经疾病,由广泛表达的管家基因GARS中的显性,有毒,功能获得性突变引起。造成了CMT2D与V型等位基因紊乱的远端脊髓性肌萎缩症区别开来的轻度至中度感觉障碍的原因。为了阐明造成潜在传入神经病理的机制,我们检查了CMT2D小鼠的感觉神经系统。我们表明,背根神经节的感觉神经元功能亚型之间的平衡被Gars突变扭曲,导致周围组织的感觉缺陷,并与总体疾病严重程度相关。 CMT2D小鼠的感觉行为发生变化,与传入失衡相伴,后者在出生时和非渐进时均存在,表明感觉神经元身份在出生前受到干扰,关键的发育损伤是传入病理的关键。通过体外实验,GlyRS突变型而非野生型GlyRS被证明与Trk受体异常相互作用并引起Trk信号转导失活,这对于感觉神经元的分化和发育至关重要。总之,这项工作表明神经发育和神经退行性机制都有助于CMT2D发病机理,因此对未来治疗的时机具有深远的影响。

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