The muscle is a major player in neuropathology of a fly model of peripheral neuropathy

What is it about?

Charcot-Marie-Tooth disease (CMT) is a nervous system disorder resulting from genetic defects in a number of different genes. The 2D subtype of CMT (CMT2D) is caused by dominant, gain-of-function mutations in a widely expressed gene (GARS) integral to the functioning of all cells, yet patients display a very specific peripheral nerve pathology (motor and sensory). Using novel fly models of CMT2D, we have shown that mutant GARS protein coming from the muscle, accumulates at the neuromuscular junction (NMJ), preceding synaptic degeneration and leading to reduced fly survival.

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Why is it important?

The genetic toolkit of flies has allowed us to probe the role of different cell types to the mechanism of NMJ degeneration in CMT2D flies. We found that muscles play an unexpected, but major, role in the neuronal defects caused by mutant GARS. Muscles and motor neurons reside in close proximity and interact both chemically and physically. This intimate partnership permits special access to sub-compartments of motor neurons for a pool of mutant GARS made by the muscle. This allows mutant GARS to aberrantly accumulate at the NMJ leading to synaptic degeneration, and provides a possible explanation for the selective pathology observed in CMT2D.