Dr James Sleigh
I am particularly interested in understanding the cause of neuronal susceptibility often observed in diseases that affect the peripheral nervous system. Motor and sensory nerves appear to be highly susceptible cells; mutations in numerous different genes important throughout the body manifest in a very specific detrimental effect on these peripheral neurons.
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. 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 cognate transfer RNA (tRNA), thereby priming the tRNA for protein translation. This housekeeping function of glycine 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?
I currently have a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship that I am using to answer this question while working in the laboratory of Giampietro Schiavo. I am using live imaging of cellular dynamics, including axonal transport, to interrogate both the motor and sensory systems in cell and animal models to better understand the cause of neuronal fragility seen in CMT2D.
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