Charcot-Marie-Tooth (CMT) disease is a group of inherited disorders that specifically affect the peripheral nerves system and is characterized by progressive muscle atrophy, sensory loss and bone deformities. This genetic disease, for which there is no effective therapy, is one of the most commonly inherited neurological disorders affecting approximately 1 in 2,500 people equating to approximately 125,000 people in the United States. Multiple mutations in four different aminoacyl-tRNA synthetase genes are causally linked to CMT. Thus tRNA synthetases are one of the largest gene families associated with CMT. This underscores the importance of tRNA synthetase in the etiology of the disease. Understanding the connection between CMT and tRNA synthetases is a challenge. Because tRNA synthetases are essential players in protein synthesis, the dogma has been that the CMT-causing mutations in tRNA synthetases must affect protein synthesis in some way. Intriguingly, CMT-causing mutations do not necessarily affect the aminoacylation function of the enzyme; and almost all tRNA synthetase mutations that are CMT-associated have autosomal dominant trait, suggesting a gain-of-function disease mechanism. Lastly, as protein synthesis is essential for all tissue types, the extreme tissue specificity associated with the CMT phenotypes has complicated the biological understanding of the role of tRNA synthetases in CMT disease. The goal of this project is to determine the disease-causing mechanism for DI-CMTC, a subtype of CMT caused by dominant mutations in tyrosine tRNA synthetase (TyrRS or YARS). Through international collaborations and a cross-disciplinary approach that combines methods of Drosophila genetics, biochemistry and cell and molecular biology, we will define the mechanism through which YARS mutations are linked to DI-CMTC. Broadly speaking, the tRNA synthetase family represents one class of DNA/RNA binding proteins that, as a whole, have emerged as an important player in neurodegenerative processes and as potential targets for therapeutic development. Thus, the mechanistic understanding we will obtain from the current study would certainly shed light on the etiology of other neurological disorders beyond CMT.

Public Health Relevance

This project will focus on studying how tyrosine tRNA synthetase is involved in Charcot-Marie-Tooth (CMT) disease, the most commonly inherited neurological disorders affecting approximately 125,000 people in the United States. The mechanistic understanding we gain from this study would also shed light on the etiology of other neurological disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS085092-03
Application #
8850921
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Nuckolls, Glen H
Project Start
2013-09-01
Project End
2018-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
$433,442
Indirect Cost
$179,464
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Blocquel, David; Li, Sheng; Wei, Na et al. (2017) Alternative stable conformation capable of protein misinteraction links tRNA synthetase to peripheral neuropathy. Nucleic Acids Res 45:8091-8104
Xu, Xiaoling; Zhou, Huihao; Zhou, Quansheng et al. (2017) An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function. RNA Biol :1-10
Atkinson, Derek; Nikodinovic Glumac, Jelena; Asselbergh, Bob et al. (2017) Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy. Neurology 88:533-542
Shi, Yi; Wei, Na; Yang, Xiang-Lei (2017) Studying nuclear functions of aminoacyl tRNA synthetases. Methods 113:105-110
Wei, Zhiyi; Xu, Zhiwen; Liu, Xiaotian et al. (2016) Alternative splicing creates two new architectures for human tyrosyl-tRNA synthetase. Nucleic Acids Res 44:1247-55
Sun, Litao; Gomes, Ana Cristina; He, Weiwei et al. (2016) Evolutionary Gain of Alanine Mischarging to Noncognate tRNAs with a G4:U69 Base Pair. J Am Chem Soc 138:12948-12955
Sun, Litao; Song, Youngzee; Blocquel, David et al. (2016) Two crystal structures reveal design for repurposing the C-Ala domain of human AlaRS. Proc Natl Acad Sci U S A 113:14300-14305
Yang, Xiang-Lei (2014) tRNA-derived G-quadruplex protects motor neurons. Proc Natl Acad Sci U S A 111:18108-9
Lo, Wing-Sze; Gardiner, Elisabeth; Xu, Zhiwen et al. (2014) Human tRNA synthetase catalytic nulls with diverse functions. Science 345:328-32
Ishimura, Ryuta; Nagy, Gabor; Dotu, Ivan et al. (2014) RNA function. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science 345:455-9

Showing the most recent 10 out of 13 publications