Paul Brehm, senior scientist at Oregon Health Science University in Portland, was awarded an MDA research grant totaling $351,648 over three years to study the underlying mechanisms of movement disorders in some forms of congenital myasthenic syndromes (CMS).

Brehm’s research team has identified zebrafish research models that carry mutations in the same proteins that are known to cause some forms of CMS in humans. In both fish and humans, these proteins are localized to the neuromuscular junction (the space where signals are transferred between nerve and muscle). Their deficiency results in movement disorders such as use-dependent fatigue (the inability to perform repetitive tasks).

In one model, known as the rapsyn-deficient line (in which the fish have mutations in the gene for the rapsyn protein), Brehm and his team have been exploring the basis of use-dependent fatigue.

Rapsyn deficiency has been associated with problems on the muscle side of the neuromuscular junction. Brehm’s team has found that the absence of an as-yet unidentified signal produced by muscle regulates the motor neuron and that, ultimately, the absence of this signal appears to be accountable for use-dependent fatigue.

Brehm’s team is working to uncover the mechanism underlying the reduced motor neuron activity that precedes use-dependent fatigue, as well as ways in which to rescue the nerve defect.

“The means to study neuromuscular function using the zebrafish system has been unparalleled among the vertebrates,” Brehm says. “The discovery of zebrafish models that carry these mutant proteins now opens the way to addressing directly the consequences in humans.”

Funding for this MDA grant began Aug. 1, 2012.