期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 16, 页码 E3324-E3333出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1614557114
关键词
aminoacyl-tRNA synthetase; Charcot-Marie-Tooth disease; distal spinal muscular atrophy type V; neuromuscular disease; neurodevelopment
资金
- Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship [103191/A/13/Z]
- French Muscular Dystrophy Association (AFM-Telethon)
- Wellcome Trust [107116/Z/15/Z]
- UK Medical Research Council
- NIH [F31 NS100328, R01NS054154, R01GM088278]
- MRC [G0601887] Funding Source: UKRI
- Medical Research Council [G0601887] Funding Source: researchfish
- Wellcome Trust [103191/A/13/Z] Funding Source: researchfish
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据