Press Release March 23, 2016

Addressing synaptic deficits at neuromuscular junctions treats Charcot-Marie-Tooth type 2D

Boosting synaptic efficacy may help alleviate symptoms for patients with a neurological condition called Charcot-Marie-Tooth type 2D (CMT2D), Jackson Laboratory (JAX) researchers and collaborators report in The Journal of Neuroscience. 

CMT is a genetic neurological disorder that causes damage to the peripheral nerves, the bundles of nerve cell fibers that connect the brain and spinal cord to muscles and sensory organs. There are several different types of the disease; CMT2D is characterized by progressive muscle weakness in the hands, loss or changes in sensation in extremities, cramps brought on by cold or exertion. 

Dominant mutations in a gene called GARS (for glycl tRNA synthetase) cause CMT2D. Disease symptoms have previously been attributed to degeneration of axons, the long “arms” of neurons that conduct electrical impulses to and from the neuron's cell body. 

However, muscle weakness, atrophy, and fatigue are also consistent with dysfunction of the neuromuscular junction (NMJ), where motor neurons transmit signals to muscle fibers. The research study, led by Jackson Laboratory Research Scientist Kevin Seburn, Ph.D., is the first to investigate the role of synaptic deficits in the NMJ in CMT2D. 

The researchers selected two mouse models for CMT2D with different mutations in the Gars gene. In mice with CMT2D, one of the mutations yields a more severe form of the disease; the other produces milder symptoms. Both mouse strains show muscle atrophy and slight abnormalities in muscle structure, possible indicators of synaptic dysfunction. And at two months of age, both strains showed changes in synaptic function, with the severe disease model displaying more profound dysfunction than the milder disease model. 

Testing two drugs with different sites of action (3,4-DAP and eserine), the researchers found that both drugs acted to increase synaptic transmission in vitro. However, only physostigmine improved performance in a test of muscle strength and endurance, reducing the animals’ CMT2D symptoms. 

Study coauthor and JAX Professor Robert Burgess, Ph.D., comments, “Synaptic dysfunction can contribute variably and intermittently to impaired neuromuscular performance, including weakness and fatigue. This suggests that drugs that improve synaptic efficacy at the NMJ should be explored as a treatment option for CMT2D patients.”

The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a National Cancer Institute-designated Cancer Center, a facility in Sacramento, Calif., and a genomic medicine institute in Farmington, Conn. It employs 1,700 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.


Spaulding et al.: Synaptic Deficits at Neuromuscular Junctions in Two Mouse

Models of Charcot–Marie–Tooth Type 2d. The Journal of Neuroscience, 36(11): 3254-3267; doi: 10.1523/JNEUROSCI.1762-15.2016