Charcot-Marie-Tooth (CMT) diseases are the most common form of hereditary peripheral neuropathies, affecting approximately 1 in 2,500 people equating to approximately 125,000 people in the United States. No effective therapy for CMT currently exists. The diseases specifically affect the peripheral nervous system and are characterized by progressive motor neuron degeneration, muscle atrophy, and sensory loss. Recent progress in neurogenetic studies has uncovered aminoacyl-tRNA synthetase as the largest gene family implicated in CMT. Among them, GARS, encoding glycyl-tRNA synthetase (GlyRS), is the first member identified and whose mutations cause a dominant axonal form of CMT (CMT2D). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons leading to deficits in distal motor function. The goal of this project is to determine the disease-causing mechanism for CMT2D. Our central hypothesis is that CMT2D-causing mutant GlyRS acquires an aberrant binding activity that directly antagonizes an essential signaling pathway for motor neuron survival, and that the toxic function of mutant GlyRS may be linked to a dysregulated, extra-translational function of wild-type GlyRS. Our hypothesis is based on our results from the previous funding period of this grant and from our collaborations with other laboratories. Through a broad range of methods from hydrogen-deuterium exchange analysis, X-ray crystallography, biochemical, and cell-based analysis to mice studies, this project will not only shed light on CMT2D causing mechanisms and open doors for developing therapeutic strategies for CMT2D patients, but also reveal important regulatory functions of GlyRSWT beyond its classic enzymatic function in protein synthesis.

Public Health Relevance

This project will focus on studying how mutations in glycyl-tRNA synthetase gene are involved in Charcot- Marie-Tooth (CMT) disease, an area with significant unmet medical needs. The study would open doors for developing therapeutic strategies for CMT patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088278-08
Application #
9544977
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Krasnewich, Donna M
Project Start
2010-09-06
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Mo, Zhongying; Zhao, Xiaobei; Liu, Huaqing et al. (2018) Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy. Nat Commun 9:1007
Xu, Xiaoling; Zhou, Huihao; Zhou, Quansheng et al. (2018) An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function. RNA Biol 15:649-658
Xu, Zhiwen; Lo, Wing-Sze; Beck, David B et al. (2018) Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function. Am J Hum Genet 103:100-114
Sleigh, James N; Dawes, John M; West, Steven J et al. (2017) Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations. Proc Natl Acad Sci U S A 114:E3324-E3333
Sleigh, James N; Gómez-Martín, Adriana; Wei, Na et al. (2017) Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis. Sci Rep 7:9216
Mo, Zhongying; Zhang, Qian; Liu, Ze et al. (2016) Neddylation requires glycyl-tRNA synthetase to protect activated E2. Nat Struct Mol Biol 23:730-7
Niehues, Sven; Bussmann, Julia; Steffes, Georg et al. (2015) Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases. Nat Commun 6:7520
Amin, Neal D; Bai, Ge; Klug, Jason R et al. (2015) Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure. Science 350:1525-9
He, Weiwei; Bai, Ge; Zhou, Huihao et al. (2015) CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature 526:710-4
Zhou, Jie J; Wang, Feng; Xu, Zhiwen et al. (2014) Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis. J Biol Chem 289:19269-75

Showing the most recent 10 out of 28 publications