MDA has awarded a research grant totaling $396,000 over three years to Shanthini Sockanathan, associate professor of neuroscience at Johns Hopkins School of Medicine in Baltimore. The new funds will help support Sockanathan’s study of motor neuron (nerve cell) development in neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).

In previous work, Sockanathan and colleagues showed that a protein called GDE2 controls the production of spinal motor neurons through extracellular glycerophosphodiester phosphodiesterase (GDPD) activity.

More recently, the team discovered that GDE2 activity is itself regulated by a second protein, Prdx1. Prdx1 activates GDE2 by breaking a particular coupling called a "disulfide bond" inside GDE2 that normally inhibits GDE2 function. Thus, the disulfide bond within GDE2 acts a molecular switch that turns motor neuron production "on" or "off." By extension, the pathways that modify disulfide bond formation play pivotal roles in the control of motor neuron differentiation (maturation).

One question that emerges from this work is: How are active forms of Prdx1 generated to ensure efficient initiation of GDE2-dependent motor neuron differentiation?

Sockanathan's study team will test the hypothesis that inactive forms of Prdx1 are reactivated through separate pathways.

In addition, building off their recent finding of another Prdx molecule that is expressed with GDE2 and inhibits its activity, the team suggests the possibility that this mechanism regulates the initiation, extent and rate of motor neuron differentiation. The team will test this theory using a combination of different approaches.

Taken together, these studies are expected to provide insight into how the pathways that modify disulfide-bond formation intersect to control the onset and progression of motor neuron differentiation.

Funding for this MDA grant began February 1, 2011.