The Burgess Lab

Neuromuscular junctions, development and disease

The Burgess Lab studies mouse models of neurodevelopmental and neuromuscular disorders. Past work includes studies on genes involved in the formation of neuromuscular junctions, and cell adhesion molecules studied in the developing retina. However, early studies using mouse genetics to discover novel genes involved in these processes also led to the identification of several excellent mouse models of rare diseases. Our current focus is on using these rare disease models to understand the underlying cellular mechanisms, to identify therapeutic targets, and to test therapies in preclinical studies. We also regularly use genome engineering to introduce additional human disease-associated variants into the mouse genome, as well as phenotype-driven approaches with spontaneous and induced mutations to identify new genes with neuromuscular and neurodevelopmental functions. 

An area of particular emphasis is inherited peripheral neuropathy, or Charcot-Marie-Tooth disease (CMT). In humans, CMT can be caused by mutations in at least 100 different genes, and we are actively working on several mouse models of CMT.  Our longest running project relates to CMT type 2D, caused by dominant mutations in glycyl tRNA synthetase (GARS). GARS encodes the enzyme that charges the amino acid glycine onto its tRNA for translation.  Interestingly, mutations in the genes encoding tRNA synthetases for at least five other amino acids also lead to forms of CMT, suggesting a common mechanism. Our recent studies showed that these mutations activate a cell stress pathway, and the chronic activation of this pathway contributes to disease severity and progression. Fortunately, this pathway can be blocked pharmacologically, and this is an effective treatment for the neuropathy in our mouse models, thus identifying a novel therapeutic target for treating these forms of CMT. In addition to the small molecule strategies, we are also actively exploring gene therapies for CMT2D and other related disorders. 

Current projects in the lab include exploring why the chronic activation of the cell stress pathway is deleterious for peripheral motor and sensory neurons, exploring novel preclinical approaches using both small molecules and gene therapy approaches, and trying to understand the why mutations in these ubiquitously expressed genes cause a disease that is specific to peripheral neurons. We are also studying other mouse models of CMT to identify disease-relevant phenotypes ranging from changes in gene expression that may identify additional therapeutic targets to changes in synaptic transmission at the neuromuscular junctions. Finally, we are developing new mouse models, including mutations related to mitochondrial protein synthesis that cause optic and peripheral neuropathy (Behr’s Syndrome) in humans. Together, these studies will help achieve our goals of understanding the underlying disease mechanisms and identifying effective ways to intervene and treat these conditions.