Michael Linhoff, a postdoctoral fellow at Oregon Health and Science University in Portland, Ore., was awarded an MDA development grant totaling $119,944 over a period of two years to study neuromuscular junction defects in congenital myasthenic syndrome (CMS).

A common cause of CMS is mutation of the RAPSN gene. This gene encodes a protein, rapsyn, that helps other proteins assemble properly on the surface of the muscle at the neuromuscular junction (NMJ). The NMJ is where the motor neuron from the nervous system contacts the muscle. The neuron releases chemicals that cause the muscle to contract.

Linhoff and colleagues have shown that a RAPSN mutation causes defects not only on the muscle, but also on the neuron where it contacts the muscle. Mutation reduces the effectiveness with which the neuron releases its chemicals, reducing muscle contraction and causing weakness.

He is studying this effect in zebrafish, a well-characterized lab model for the study of the interaction between nerve and muscle. “Our lab previously identified a mutant fish line [with a mutation in the RAPSN gene], called twitch once, that exhibits use-dependent fatigue similar to patients with CMS,” Linhoff says.

He will be using high-resolution imaging technologies to study the mechanisms underlying the dysfunctions seen in the twitch once fish. Using the images, he will develop three-dimensional models of the zebrafish neuromuscular junction to discover the details of the neuronal defect caused by the mutation.

“Determining the molecular mechanisms underlying this dysfunction may yield potential therapeutic targets to correct use-dependent fatigue in patients with congenital myasthenias,” Linhoff says.

Funding for this MDA grant began Feb. 1, 2013.