Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology.
Hum Mol Genet 2015 Aug 1; 24(15):4397-406.
Charcot-Marie-Tooth (CMT) neuropathies are collectively the most common hereditary neurological condition and a major health burden for society. Dominant mutations in the gene GARS, encoding the ubiquitous enzyme, glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and lead to CMT disease type 2D. This genetic disorder exemplifies a recurring motif in neurodegeneration, whereby mutations in essential, widely expressed genes have selective deleterious consequences for the nervous system. Here, using novel Drosophila models, we show a potential solution to this phenomenon. Ubiquitous expression of mutant GlyRS leads to motor deficits, progressive neuromuscular junction (NMJ) denervation and pre-synaptic build-up of mutant GlyRS. Intriguingly, neuronal toxicity is, at least in part, non-cell autonomous, as expression of mutant GlyRS in mesoderm or muscle alone results in similar pathology. This mutant GlyRS toxic gain-of-function, which is WHEP domain-dependent, coincides with abnormal NMJ assembly, leading to synaptic degeneration, and, ultimately, reduced viability. Our findings suggest that mutant GlyRS gains access to ectopic sub-compartments of the motor neuron, providing a possible explanation for the selective neuropathology caused by mutations in a widely expressed gene. Hum Mol Genet 2015 Aug 1; 24(15):4397-406.
Grice, Stuart J; Sleigh, James N; Motley, William W; Liu, Ji-Long; Burgess, Robert W.; Talbot, Kevin; and Cader, M Zameel, "Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology." (2015). Faculty Research 2015. 113.