October 18, 2006

Research Update — from ALSA’s National Office
Role of Specific Cells in New Lab Models of ALS Will Hasten Advances
Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator

[Quick Summary: Findings reported at the Society for Neuroscience meeting in Atlanta, Ga., show how scientists are creating new laboratory models that will allow therapeutic progress in ALS. The investigators are using the models to clarify the roles of specific cells in the disease process.]

A fish can show aspects of the disease process in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) opening the way to screen for new drugs that could repair the defects revealed in the fish as nerve fibers grow to reach muscles, according to researchers presenting October 17 at the Society for Neuroscience Meeting in Atlanta.

Zebrafish are proving useful as tools for scientists. They serve as an easily manipulated, simple organism with well defined genetics. Now the fish show what may happen early in ALS, and how the action of other genes might either help or add to the damage in this disorder of the nervous system.

Belgian researchers working with Wim Robberecht, M.D., Ph.D., at the Katholieke Universiteit, Leuven, showed that inserting the gene for the mutant proteins responsible for some inherited cases of ALS produces a defect in the way motor nerve cells grow in the embryonic fish. These motor neurons are cells that die in the disease. The long fibers or axons of the motor neurons were shorter and failed to branch as extensively as normal in the developing mutant zebrafish.

The defect was most pronounced with a particular gene change in the protein, copper-zinc superoxide dismutase (SOD1), the same mutation (A4V change in SOD1) that produces an especially aggressive form of ALS.

With this new lab model of the disease in hand, the researchers can begin to screen libraries of compounds for a potential therapeutic that might help correct the axon defect and look for the action of other genes that could modify the disease process in the fish. A surprising number of the genes in zebrafish have counterparts in people.

Other New Models of ALS

In other progress toward new model systems to study ALS, investigators added new information at the meeting October 17 on a mutation in an axon protein. The p150Glued mutation, as presented last year at the Society for Neuroscience Meeting, produces a motor neuron disease in mice. This is a mutation that changes the protein called dynactin, which in axons helps move key supplies to the endings at muscle. The team working at Johns Hopkins, led by Philip Wong, Ph.D., showed that the gene change most likely produces a toxic effect. The mice show abnormal deposits in their motor neurons, similar to what happens in ALS. Also, this genetic change can be introduced into fruit flies. The p150Glued mutant flies show a flight defect, followed by paralysis and shortened life span, Hopkins investigators led by Alex Kolodkin, Ph.D., reported.

Which Cells Have the Damage in ALS?

The ability to have the gene for mutant SOD1 expressed only in certain cell types in living animals is also a promising way to study what might happen in ALS. By clarifying the role of each cell in the nervous system in producing the disease, researchers are paving the way to a therapeutic approach, in which drugs might be targeted to specific cells and the processes they mediate.

At the October 17 meeting, the roles of different types of cells in the disease process were a focus of several presentations. **** Jaarsma, Ph.D., and colleagues at Erasmus Medical Center, Rotterdam, The Netherlands, showed that a mouse with mutant SOD1 expressed only in the motor neurons shows all of the features of the disease.

Chein-Ping Ko, Ph.D., at the University of Southern California, has been testing whether muscle itself can play a role in ALS, in research funded by The ALS Association. They found delay in loss of motor function in mice that had the SOD1 mutation and also lacked a gene that produces a protein called myostatin. Myostatin normally keeps muscle size in check. These double mutant mice had more muscle at the end stages of disease than is typical in SOD1 mutant mice. Preserving the muscle mass might be beneficial in ALS to aid quality of life.

Ko noted that Erika Holzbaur, Ph.D., and colleagues at the University of Pennsylvania, have developed an antibody to inhibit myostatin, a treatment that increased muscle mass and strength up until the late stage of disease in SOD1 mutant rodents. The antibody treatment did not extend lifespan, as published in September 2006 in Neurobiology of Disease.

Another molecule called follistatin that can increase muscle mass did not help prolong survival or grip strength in the mouse model of ALS, as reported in a talk October 17 by Brian Kaspar collaborating with Don Cleveland. These researchers delivered the muscle promoting protein by a gene therapy to the muscle in SOD1 mice. They also showed by silencing the gene producing the mutant SOD1 in muscle did not affect the disease course, but silencing SOD1 production in both motor neurons and muscle (using siRNA) maintained grip strength in the mice.

Evidence that muscle is not the direct player in ALS damage is that a transplant of muscle from a SOD1 mutant animal will accept healthy nerves in a normal animal. The team of Martin Pinter, Ph.D., at Emory University that presented these findings collaborated with Kevin Seburn, Ph.D., at the Jackson Laboratories in Bar Harbor, Maine. It is possible that muscle might respond to therapeutic intervention and is not itself generating the damage in ALS.

So What Is Toxic in ALS?

Spinal cord tissue carries a toxic action in the disease, as cord tissue culture from mutant SOD1 mice was toxic to motor neurons derived from stem cells and living in dishes in the lab, reported by a group of investigators at Johns Hopkins led by Douglas Kerr, M.D., Ph.D. The researchers demonstrated that the growth of axons is impaired by a set of molecules present in higher amounts in the spinal cord tissues that are linked to inflammation. By inhibiting the action of these pro-inflammatory and oxidizing molecules, the researchers were able to improve the ability of the motor neurons to grow their axons.

Please see the research web pages at www.alsa.org for further information about the roles of laboratory models (http://www.alsa.org/research/article.cfm?id=812) and specific cell types (http://www.alsa.org/research/article.cfm?id=823) in ALS.

http://www.catfishchapter.org/news/Atlanta06.html