# Link extracellular function of tRNA synthetase with pathological mechanism of disease

> **NIH NIH R35** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $460,000

## Abstract

Abstract
Aminoacyl-tRNA synthetases (aaRSs) are a family of essential enzymes that catalyze the first
reaction in protein biosynthesis, namely, the charging of transfer RNAs (tRNAs) with their cognate
amino acids. Due to the importance of protein synthesis in most cells, it is not surprising that
almost all aaRSs family members have been linked through bi-allelic mutations to human
diseases that often affect multiple organ systems. Interestingly, human aaRSs also have wide-
ranging non-enzymatic functions regulating many important biological processes. Therefore, in
principle, regulatory functions of aaRSs could also be involved in the disease mechanism.
However, the challenge lies in the difficulties to dissect the impact of regulatory functions from
that of the enzymatic roles. In addition to being in the cytosol where protein synthesis occurs,
aaRSs are frequently detected in the extracellular space, such as in cell culture media and in the
systemic circulations of humans and mice. Yet, the physiological significance of extracellular
tRNA synthetases remains unknown. This project aims to investigate pathophysiological function
of extracellular tRNA synthetases. We focus on a selective group of aaRSs linked to a specific
neurodegenerative disease – Charcot-Marie-Tooth disease (CMT) – through dominant mono-
allelic mutations. Under the support of GM for the last 10 years, we established that the
extracellular presence of glycyl-tRNA synthetase (GlyRS or GARS; the first and the most
prominent CMT-linked aaRS) is relevant to the disease and we identified specific cell signaling
pathways dysregulated by CMT-causing GlyRS mutants. Our future research will investigate the
involvement of a particular signaling pathway in all aaRS-linked CMT subtypes and uncover
extracellular roles of aaRS in the normal cell signaling process.

## Key facts

- **NIH application ID:** 10849701
- **Project number:** 5R35GM139627-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Xiang-Lei Yang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,000
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849701

## Citation

> US National Institutes of Health, RePORTER application 10849701, Link extracellular function of tRNA synthetase with pathological mechanism of disease (5R35GM139627-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10849701. Licensed CC0.

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