The fundamental question driving my research is how do mutations in widely expressed genes cause selective peripheral nerve deterioration? Mutations in many different genes required throughout the body manifest in a very specific detrimental effect on motor and sensory nerves, and I want to better understand the molecular and cellular mechanisms that cause this. Charcot-Marie-Tooth disease (CMT) is a large group of genetically diverse peripheral neuropathies that share the principal pathological feature of progressive motor and sensory impairment leading to muscle weakness and sensory defects. CMT type 2D (CMT2D) is caused by dominant, toxic gain-of-function mutations in a gene called GARS, which encodes glycyl-tRNA synthetase (GlyRS). GlyRS attaches the amino acid glycine to its partner transfer RNA (tRNA), thereby priming the tRNA for protein translation. This housekeeping function of aminoacylation explains the widespread and constitutive nature of GARS expression, but how do mutations that affect a protein found in all cells selectively trigger peripheral nerve degeneration?

Using CMT2D as a paradigm, my laboratory is studying causes of motor and sensory nerve degeneration and the mechanisms underpinning the dynamic process of axonal transport. By improving understanding of neuropathic pathways and associated pathologies, we aim to generate effective, pre-clinical gene therapies for genetic peripheral nerve diseases.