August 1, 2006
Research Update — from ALSA’s National Office
The ALS Association Searches for New Genes and Probes Disease Process in ALS
Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator
Funded projects by The ALS Association for fall 2006 will hasten progress toward effective therapies for ALS. The projects promise key advances in understanding of the biology of the disease and sew together common threads into a more complete picture of the roles of axonal damage, surrounding cells in the nervous system, and how stem cell or trophic factor therapies might succeed. An emphasis is on new genetic information that will reveal potential targets at which to aim drug candidates.
Funding of a total of $1.8 million will support eight investigators just entering the field of ALS research, with starter grants of a year’s duration, and ten grants that go to multi-year efforts to move forward in the search for effective treatment of what is still, inevitably, a fatal disorder.
Casper Hoogenraad, Ph.D., and Dick Jaarsma, Ph.D., of Erasmus Medical College, Rotterdam, The Netherlands, propose to create a mutant mouse to study a form of ALS with mutation in a gene called VAP-B (vesicle associated membrane protein associated protein B). Scientists are not yet sure what this protein does, but the mutation likely changes the protein’s shape. Creating a mouse with the mutation should produce signs of motor neuron disease and by comparison with other mouse models of ALS could suggest approaches toward a treatment.
Vincenzo Bonifati, M.D., Ph.D., and Ben Oostra, Ph.D., of Erasmus Medical College, Rotterdam, The Netherlands, are working with cases of ALS found in a small Dutch village and are attempting to find the responsible gene change for the presumably inherited condition there. Providing a new genetic reason for ALS should help therapeutic approaches for all forms of the disease.
Miriam Meisler, Ph.D, of the University of Michigan, Ann Arbor, has found a mutation in one of the proteins that helps keep crucial cellular supplies flowing properly within the long fiber of nerve cells. The mutation is present in a mouse with a motor neuron defect called the wobbler mouse. She proposes to study the function of the normal protein made by the gene, called VPS54, in mice and to see if people with ALS might also have mutations in this protein. One ALS patient has already been found with this gene change.
The mutation in the wobbler mouse is also under investigation by Thomas Schmitt-John, Ph.D., at Aarhus University in Denmark, who will search for gene changes in sporadic ALS patients that could affect vesicles, the sacks within cells that move materials about while protecting them from powerful enzymes present inside cells. Gene changes affecting vesicles might explain at least some instances of ALS and provide a new target for design of therapeutics.
Minh Dang Nguyen, Ph.D., of the University of Calgary in Alberta, Canada, has discovered a new protein that helps keep neurons intact. Through a partnership with The ALS Society of Canada, his group will seek a role for this protein, called Ndel1, in the health of motor neurons—the Ndel1 protein apparently interacts with other proteins that are known to support growth and maintenance for the long fibers of neurons. If implicated in ALS, the Ndel1 protein could prove to be a useful target for ALS therapeutics.
Professor Kay Davies, D.Phil., of the University of Oxford, U.K., and colleagues propose ALS might involve the special cells that form an insulating sheath around nerve fibers. In ALS, damage appears first at the junction of nerve and muscle rather than at the cell body, so the so- called Schwann cells that make insulating myelin of nerves might be involved. The researchers will generate mice that make the mutant protein, copper-zinc superoxide dismutase (SOD1), only in the myelin forming Schwann cells. The mutated SOD1 presumably would affect the course of disease if its action in the Schwann cells is critical in ALS.
Karl Kasischke, M.D., and Maiken Nedergaard, M.D., Ph.D., at the University of Rochester, New York, are collaborating to develop a new way to see into the brain of lab rodents in order to follow changes that reflect motor neuron disease. The researchers will work back toward the beginning of the disease process in order to see how the damage is initiated and how the neurons and neighboring support cells of the nervous system might interact to produce damage to the motor neurons. Their technique, called multiphoton imaging, involves microscopic sized lenses that are small enough to enable this approach in living animals.
Microglia, the immune cells of the brain and spinal cord, play a role in ALS, but the reasons are not yet clear. Michael Carroll, Ph.D., of the CBR Institute for Biomedical Research in Boston, studies how microglia play a part in the inflammatory response to low tissue oxygen and other stress. His lab group will work with the microglia from mice that have the mutation linked to some inherited forms of ALS. They will also introduce this SOD1 mutation into normal microglia. A comparison in lab dishes of the behavior of normal microglia with those collected at various time points in the disease might reveal key differences that contribute to the disease process.
Gerry Shaw, Ph.D., and David Borchelt, Ph.D., of the University of Florida, Gainesville, find that a particular protein of the nerve fibers shows up in the blood in rats that have damaged nerves, so it might serve as a potential marker of nerve injury. Indeed this marker appears to be present in the SOD1 mutant rodents that show many aspects of ALS. The investigators will look at the time course of the appearance of this molecule, a part of the scaffold inside nerve fibers called phosphorylated heavy neurofilament (pNF-H), in rats. They will see if this protein is present in blood samples from ALS patients with SOD1 mutation and those who have the mutation but are not having any symptoms of ALS.
Diagnostic imaging is a promise yet unmet for ALS. Jonathan Katz, M.D., and Michael Weiner, M.D., of the Forbes Norris MDA/ALS Research Center and the VA Medical Center, respectively, in San Francisco, propose to follow ALS patients with two imaging studies timed six months apart to see if they can document changes in the brain that correlate to changes in cognition. With magnetic resonance imaging (MRI) using a powerful magnetic field, they hope to pinpoint areas of the brain that reflect such changes and could serve as a biomarker of ALS.
Sanjay Kalra, M.D., and his collaborators at the University of Alberta in Edmonton, Canada, also intends to document brain changes with ALS with partnership funding with The ALS Society of Canada. An MRI approach can see changes in the brain’s chemical messengers, glutamate and GABA (gamma amino butyric acid). They propose that measuring this chemistry of the brain in specific areas governing the cognitive changes in ALS could serve as a marker of disease progress and potentially gauge therapeutic effects.
Disease Process of ALS
The finding that ALS affects cognition in many instances leads neurologists Michael Strong, M.D., at the Robarts Research Institute in London, Ontario, Canada, and P. Nigel Leigh, M.D., Ph.D., at the Institute of Psychiatry, King’s College, London, U.K., to propose a thorough investigation into brains donated for research to document differences in ALS. These donated brains are unique in that the ALS patients were followed clinically for cognitive change. These researchers on both sides of the Atlantic will look for altered brain cell counts and changed proteins such as tau and ubiquitin that are suspect in ALS.
A third partnering grant with The ALS Society of Canada will support Christopher A. Shaw, Ph.D., University of British Columbia, Vancouver, Canada, and colleagues who are seeking any role for potentially toxic compounds found in cycad seeds that have been proposed as linked with the type of ALS found on the island of Guam. They will see whether these compounds, or their byproducts after metabolism, are present in higher levels in the blood of ALS patients. They will test for toxic effects of different amounts of the so-called sterol glucosides found in the seeds and see if they can block any toxicity with available drugs.
Jonathan D. Glass, M.D., of Emory University in Atlanta, is investigating which of the myriad proteins in the neuron are affected during ALS by monitoring the entire set of proteins produced in spinal cord cells of the mouse model of ALS, the SOD1 mutant. They will carry out a preliminary investigation using state of the art mass spectroscopy to find any proteins that change in amount specifically during disease onset and progression. Such changes could produce therapeutic leads.
Apoptosis and the Mitochondria
Piera Pasinelli, Ph.D., and Davide Trotti, Ph.D., have found that the mutant SOD1 protein binds to another protein, called Bcl-2, which plays a role in cell death. This is the normally orchestrated removal of old or unneeded cells called apoptosis. They will see how the mutant protein, SOD1, linked with some inherited forms of ALS, interacts with the Bcl-2 protein.
A new funding opportunity through The ALS Association is provided by The Alan L. Phillips Discovery Grant Award, made possible through support from Morton and Malvina Charlestein, with the first award going to Robert Burgess, Ph.D., at The Jackson Laboratory, Bar Harbor, Maine. Burgess will engineer mice to make the SOD1 mutant protein with a tag that brings the damaged protein specifically to the mitochondria. This will directly test if the toxic site of mutant SOD1 action is indeed the mitochondria. This idea would be supported if the mice making mutant SOD1 at the mitochondria develop motor neuron disease earlier.
Wim Robberecht, M.D., Ph.D., and colleagues at the Flanders Interuniversity in Antwerp, and at University Hospital Gasthuisberg in Leuven, Belgium, are studying how motor neurons deal with the possibly toxic excess of glutamate and how this can contribute to ALS. They have found that the surrounding glial cells called astrocytes can regulate how motor neurons handle glutamate. The helping molecule called VEGF (vascular endothelial growth factor) also appears to influence glutamate balance. Both processes may act at the same part of the receptor for glutamate (abbreviated as GluR2). The researchers seek to explain how the GluR2 molecule may mediate many aspects of the biology of the disease process in ALS and how therapeutic efforts directed there might best succeed.
Xue-Jun Li, Ph.D., of the Waisman Center at the University of Wisconsin in Madison, will seek to generate motor neurons of the brain from embryonic stem cells. The use of mouse cells to study how motor neurons might be generated, and survive for effecting repairs, will provide insights into possible therapies for ALS and will allow for screening of new drug candidates. This project is now possible due to the ability to generate spinal motor neurons from stem cells and new information about how cortical motor neurons are formed in the developing brain; much of this progress funded through support by The ALS Association. Further progress will no doubt follow from this round of funding.
