期刊
DISEASE MODELS & MECHANISMS
卷 2, 期 7-8, 页码 359-373出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.002527
关键词
-
资金
- Amyotrophic Lateral Sclerosis Association
- Brain Research Trust
- European Commission [NEST-2003-1, 12702]
- Medical Research Council (UK)
- UK MRC Centre for Neuromuscular Disease [G0500288]
- Motor Neuron Disease Association
- National Institutes of Health [NS054154]
- Robert Packard Center for ALS Research at Johns Hopkins
- Wellcome Trust (UK) [076700]
- MRC [G0601887, MC_U142684173, MC_U142684175, MC_U142684172, G0601943, G0500288] Funding Source: UKRI
- Medical Research Council [G0500288, MC_U142684173, MC_U142684175, MC_U142684172, G0601943, G0601887] Funding Source: researchfish
Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, Gars(C201R), with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The Gars(C201R) mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.
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