National Institute of Neurological Disorders and Stroke 5R37NS054154-17

The Genetics of the Neuromuscular Junction: Mechanisms and Disease Models

NIH-funded research project investigating genetic mutations in tRNA synthetase genes causing peripheral neuropathy, focusing on disease mechanisms and potential gene therapy and pharmacological treatments.

Description

This project examines dominant mutations in tRNA synthetase genes that cause inherited peripheral neuropathy. The research aims to understand the biochemical and cellular basis of these diseases, test mechanisms explaining their specificity for motor and sensory neurons, and evaluate pharmacological and gene therapy treatments. The study focuses on mutations in glycyl- and tyrosyl-tRNA synthetase (Gars and Yars) in mouse models, which activate the integrated stress response (ISR) via GCN2 kinase. The hypothesis suggests that mutant synthetases have increased affinity for their cognate tRNAs, sequestering them and causing ribosome stalling during translation, leading to disease. The project includes measuring synthetase-tRNA affinities, developing human cell models, and testing pharmacological inhibition of ISR.

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