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James N. Sleigh

MBiol, DPhil


Sir Henry Wellcome Postdoctoral Fellow

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My connections

Neuromuscular junctions

The fundamental question at the centre of my research is how do mutations in widely expressed genes cause highly selective peripheral nerve deterioration? Mutations in numerous different genes important 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 causing 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. 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. 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 define the impaired pathways linking GARS mutations to peripheral neurodegeneration.

Dorsal root ganglion

Biography

I received my undergraduate Masters in Biology (MBiol) from the University of Bath (2005-2009), which included a year at Harvard Medical School (2007-2008) researching the neuromuscular disease spinal muscular atrophy (SMA). I then completed my MRC-funded DPhil at the University of Oxford (2009-2012), extending my work on SMA, while studying a number of other disorders impacting peripheral motor and sensory nerves. From 2012-2014, I worked in the laboratory of Dr. Zameel Cader on the genetic peripheral neuropathy Charcot-Marie-Tooth disease type 2D (CMT2D). I am now a Wellcome Trust-funded Sir Henry Wellcome Postdoctoral Fellow continuing my work on the mechanisms underlying CMT2D.

Soleus muscle