October 2006
ALS Research News (A monthly summary of significant articles about ALS research)
Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator
While this summary is not exhaustive, it does include some of the most recent advances. If you would like certain news items featured, please contact the Research Department at researchgrants@alsa-national.org.
Myostatin Inhibition Slows Muscle Loss in Rodent Models of ALS
A molecule that regulates muscle growth might be a target for ALS therapeutics that could improve quality of life, according to research published in September in Neurobiology of Disease. As reported by Erika Holzbaur, Ph.D., collaborating with researchers at Wyeth, muscle mass is preserved by inhibiting the action of myostatin by a specific antibody. Mice retained strength longer with the treatment, even though they expressed a mutation to the protein, copper-zinc superoxide dismutase (SOD1). The antibody however did not affect onset or survival time of the SOD1 mutant mice. The mutation is linked to an inherited form of ALS. The fact that the treatment also preserved diaphragm muscle suggests a role in maintaining quality of life in ALS. Similar findings with myostatin were reported at the meeting this month of the Society for Neuroscience.
Stem Cells Survive and Make Contacts in SOD1 Rats
Human stem cells survived and slightly delayed onset of disease in SOD1 rats, according to published findings by a team at Johns Hopkins University in Baltimore, Md., led by Vassilis Koliatsos, M.D. As reported in Transplantation in October, the rats showed twice as many motor neurons surviving at 128 days, a time when symptoms are apparent in these transgenic animals. Their motor strength was retained a week or two longer than SOD1 rats not receiving live cell transplant into the lumbar spinal cord. Survival was prolonged by a week or two. The results suggest that stem cell therapy might be feasible in ALS but may work by delivery of supportive, trophic molecules rather than by repair of functioning connections to muscle. Human testing is still far off, the researchers noted in a press statement.
Details on ALS Patients with Mutation in CHMP2B Protein Involved in Cellular Dynamics
A mutation that is newly described for some people with the cognitive changes called frontotemporal dementia (FTD) also occurs in at least a few cases of ALS, British researchers and collaborators published in Neurology in September (the report was available online in June). The change in the gene coding for CHMP2B (charged multivesicular body protein 2B) was discovered in two ALS patients who had primarily weakness in the lower motor nervous system, according to the report by Paul Ince, M.D., University of Sheffield, U.K. Only one had symptoms of FTD. Abnormal deposits of protein appeared in the support cells of the nerve fibers, called oligodendroglia. The mutation affects a protein that handles the flow of materials within cells. Cell and nerve fiber dynamics have been implicated in ALS, as mutations to key proteins in these processes are found in certain cases of the disease. Watch for the summary of The ALS Association sponsored workshop on Axon Dynamics.
New Probe of Mitochondria Show Changes in Oxidation
Processes within the mitochondria, the power plants that fuel cellular metabolism, are able to produce reactive oxygen that is implicated in many disorders including ALS. Researchers at Oregon State University, working with Joseph Beckman, Ph.D., published in the Proceedings of the National Academy of Sciences on a more accurate way to see inside the mitochondria and watch production of potentially toxic oxygen, using a fluorescence microscope and a chemical probe. The technique to monitor superoxide was published online October 2.
Protective Compound Promising in Lab Dishes
Beckman in collaboration with an international team led by Luis Barbeito, M.D., of the Institut Pasteur de Montevideo, Uruguay, meanwhile showed that a compound that can affect cell death, which may be killing motor neurons in ALS, works through some actions of the helper molecule, nerve growth factor. The new compound, with the code name LM11A-24, protects nerve cells growing in lab dishes. These cells are protected against the toxicity caused by adding spinal cord tissue taken from SOD1 mice. These findings were published in September in the European Journal of Neuroscience.
Nerve Fibers Respond to Specific Trophic Factors
The growth of nerve fibers from the cells in the cortex that go out through the spinal cord to muscles and that die in ALS responds to distinct messages from particular helper molecules, the trophic factors IGF-1 and BDNF. IGF-1 (insulin like growth factor 1) tells the fibers to extend in length, while brain derived neurotrophic factor (BDNF) tells the endings of the fibers to branch out. These different effects were demonstrated in cortico-spinal motor neurons isolated and grown in lab dishes, by Jeffrey Macklis, M.D., D.HST,, and colleagues at Harvard, as reported online in October and in print in November in Nature Neuroscience. The effects on axon growth and branching are distinct from the known ability of these trophic factors to help neurons to survive.
VEGF Variants and Sporadic ALS
Variations in the coding for the gene that directs cells to make the helper molecule, vascular endothelial growth factor (VEGF), do not give any changes in the risk of developing sporadic ALS. These findings in a family based study design contradict earlier findings from a case control design study that suggested a link to ALS with certain changes in the coding of the VEGF gene. The lack of association was published in Neurology in August by a team led by Teepu Siddique, M.D., at Northwestern University, Chicago.
In October in Neurology, the French ALS Study group reported that the SMN1 gene involved in a genetic, childhood onset motor neuron disease is possibly a risk factor in ALS that does not run in families. ALS is linked to having an abnormal number of copies of the SMN1 gene in a comparison of the genetic profile of 600 ALS patients and a similar number of unaffected people. The SMN2 gene which modifies the severity and onset of spinal muscular atrophy does not appear to play a role in ALS. Another study had reported the converse, with the SMN2 gene showing increased frequency of gene deletions in ALS but the SMN1 gene lacking any difference in ALS patients compared to controls. The gene is involved in assembling the ribosomal proteins, the cellular factories that produce all proteins in the cell. The team includes researchers Phillippe Corcia, M.D., Ph.D., at the Universite Francois-Rabelais in Tours, and Christian Andres, M.D., Ph.D., at INSERM, Tours.
Normal Glial Cells Help Mutant SOD1 Mice
Infusing normal glial cells into SOD1 mutant mice helps their disease, according to a report by Stanley Appel, M.D., and colleagues at Methodist Neurological Institute, Houston. As published in the Proceedings of the National Academy of Sciences, a bone marrow transplant to the mice that contained genetically normal glial cells prolonged lifespan of SOD1 mice by 40 percent. The treatment also slowed loss of motor neurons. Conversely, mice lacking their own microglia but transplanted at birth with SOD1 mutant microglia grew more slowly than those given normal microglia but did not have motor symptoms. This report highlights the role of the microglial cells in the progress of ALS, though they are not alone responsible for the disease.
