9/21/2007
Joint Project Brings Expertise to Bear on ALS Axon Dynamics
[Quick Summary: A new collaboration among ALS experts will focus on abnormal dynamics of material transport along nerve fibers in the disease using models of the disease in rodent, worm, and squid tissues.]
Abnormal axonal dynamics, a key feature of the disease amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s Disease), will be the focus of a multidisciplinary project funded by The ALS Association with collaboration among clinicians and basic scientists at different institutions in the Chicago area. The joint effort will build on recent advances and bring to bear new techniques to model the disease in simple laboratory systems in order to identify promising therapeutic routes.
Investigators Raymond Roos, M.D, University of Chicago, Richard Morimoto, Ph.D., Northwestern University, and Scott Brady, Ph.D., University of Illinois, Chicago, will collaborate in this effort funded by the program of The Association that aims to recruit and retain experts to the challenge of ALS research. Roos says that he and his colleagues “are excited about this collaboration, which really only came about as a result of The Association. It brings together individuals with very different backgrounds and expertise, different labs, and different institutions. This kind of interdisciplinary collaborative approach provides a synergy to move the research along as quickly as possible.”
Mice making mutant copper-zinc superoxide dismutase (SOD1), the protein altered in some inherited cases of ALS, provide a way to find out what goes wrong in the disease and a way to test therapies. But simpler model systems complement this established ALS model. Morimoto has developed a worm that also makes the mutant protein and shows certain changes as a result of the presence of altered SOD1—as the worm is transparent, these changes are easily viewed under the microscope.
Brady’s team, including assistant professor of Anatomy and Cell Biology, Gerardo Morfini, Ph.D., has demonstrated that the flow of materials along the nerve fiber can be changed due to mutant SOD1 known as axonal transport. They can see this under a microscope after extruding the insides of the squid giant axon. This set-up provides a way to view nerve fiber dynamics with cell components that can still function together biochemically on a microscope platform. Using this approach, they have identified kinase activities that are altered by mutant SOD1 and affect this axonal transport.
The new collaborative project will undertake the goals of finding out if existing drugs that alter controlling molecules that regulate the flow along nerve fibers can counter the change in material traffic induced by mutant SOD1. If so, this could provide a platform for therapeutic investigation.
The investigators will see if the mutant worm model has changes in nerve fiber dynamics when mutant SOD1 is present, and what molecules might modify this to identify therapeutic targets.
Roos is working with phage (viruses that infect bacteria) to identify molecules that interact with mutant SOD1 and might prevent it from working normally, for instance, if the molecules are trapped in the apparently toxic aggregates the mutant protein produces within cells; molecules and antibodies identified in the phage display experiments will be tested for their effect in the worm, squid and mouse mutant SOD1 models.
As drugs already exist to affect kinases, including some in clinical testing in other diseases, the collaboration could yield rapid progress towards new therapeutics for ALS.
Learn more about axon dynamics and laboratory models in ALS.
Funding for this research also has been made possible by the State of Illinois, which this year provided $1 million to The ALS Association to support and expand ALS research programs. Led by Chicago Chapter Board Chair, Tobin Kucharski, The ALS Association has partnered with state leaders in Illinois, including House Speaker Michael Madigan, as the state has directed a total of $4 million over the previous three years to support The Association’s research programs.
