August 2006

ALS Research News (A monthly summary of significant articles about ALS research)

Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator

How Inflammation Plays Out in ALS
Why Aging Might Bring on Diseases Such as ALS
Are ALS Patients Living Longer?
ALS Messenger RNA: Lack of Adhesion in Nervous System
Brain Chemistry Predicts Survival in ALS
VAPB Mutation in ALS
Stem Cell Reservoir Altered but Still Working in ALS Mice
Potential to Harvest Embryonic Stem Cells without Harm
A Recipe to Revive Stem Cell Characteristics in More Mature Cells

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.

How Inflammation Plays Out in ALS

A role of inflammation in ALS is clarified by research published in the Proceedings of the National Academy of Sciences in August by Serge Przedborski, M.D., Ph.D., and colleagues at Columbia University. The team found that an enzyme activated during inflammation produces reactive products that damage proteins involved in orchestrating cell death. Specifically, action of the enzyme called NADPH oxidase ends up damaging the insulin like growth factor, IGF-1, that helps maintain motor neurons and also puts programmed cell death into action. Stopping the action of NADPH oxidase extends survival in a model of ALS, mice that express the mutated protein copper-zinc superoxide dismutase (SOD1), which is responsible for some inherited forms of the disease.

Why Aging Might Bring on Diseases Such as ALS

Salk Institute researchers and collaborators at the Scripps Lab in La Jolla, Calif., published online in Science in August evidence that aging cells falter in their ability to protect against defective protein. The common theme appears in findings from a lab roundworm called C. elegans. Protective steps are taken by the so-called insulin/IGF-1 pathway, which can package damaged protein and render it harmless, but the process becomes impaired as humans and worms age. The findings were with the damaged protein that produces Alzheimer’s disease, as reported by Andrew Dillin, Ph.D., and colleagues. A model of ALS in C. elegans is funded through The ALS Association to find out how aggregates of SOD1 behave and test drugs to stop their toxicity.

Are ALS Patients Living Longer?

Researchers working with Stanley Appel, M.D., formerly at Baylor University in Houston, Texas, published in August in the Archives of Neurology on the question of whether patients with ALS are surviving longer. They show that patients diagnosed after 1999 lived longer on average than those diagnosed prior to this year. Contemporary patients progressed more slowly on average taking ten months as compared to nine months to read a 20 point change on the Appel score, a rating scale for ALS progression. The investigators note that improved, multidiscipline disease management of ALS or perhaps better care of concurrent medical conditions might explain the difference.

ALS Messenger RNA: Lack of Adhesion in Nervous System

Michael Strong, M.D., and colleagues reported in August in the Neurobiology of Disease that the messenger RNA (mRNA) from normal mice that carries out construction of SOD1 will form a complex with protein, but this does not happen in tissues other than the nervous system. Something is special about the cells of the nervous system for this interaction of SOD1 mRNA as the interaction does not take place in other tissues. The special aspect of this interaction for nerve tissues could point to an explanation of why ALS damages motor neurons. Especially so, as mutant SOD1 fails to form these complexes but only when the gene change in the SOD1 instructions is one that produces ALS. Other mutations to SOD1 that do not produce ALS do not change the ability of the mRNA to link up with protein in the nerve cells.

Brain Chemistry Predicts Survival in ALS

Canadian researchers Sanjay Kalra, M.D., Douglas Arnold, M.D., and collaborators at the University of Alberta, published on measures obtained by imaging the brain that show a relationship to rate of progression of ALS. As published on line in July in the Journal of Neurology, Neurosurgery, and Psychiatry, a chemical signal, called the ratio of N-acetylaspartate (NAA) to choline, indicates damaged neurons on brain imaging. Patients with ALS who showed this ratio as a lower amount went on to progress more rapidly compared to patients with higher NAA to choline ratios. The ALS Association will be funding further studies that include this measure to see if it will be reliable as a marker of the disease and how fast it progresses.

VAPB Mutation in ALS

Italian researchers at the Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, published in May in the Journal of Negative Results in Biomedicine that mutation in the gene for VAMP/synaptobrevin-associated membrane protein B (VAPB) is not a cause of ALS in their local population in southern Italy. A mutation in this protein is linked to ALS, but it apparently is a rare reason for the disease. Different genetics may be linked with the disease in different populations as has been reported for associations between variants of the genes for vascular endothelial growth factor (VEGF) present along with ALS more frequently but in only some places of the world. The Italian team was headed by Aldo Quattrone, M.D.

Stem Cell Reservoir Altered but Still Working in ALS Mice

Lee Martin, Ph.D., and colleagues at Johns Hopkins find that some changes occur in the properties of stem cells present in the brains of mice when those mice also express the SOD1 mutation. However, the mice still have these intrinsic stem cells present in their brains, and these stem cells do appear to be able to respond to many signals to multiply and form new neurons. Their report appears in the July Journal of Comparative Neurology.

Potential to Harvest Embryonic Stem Cells without Harm

Researchers may be able to pluck out a single stem cell and multiply it in lab dishes without harming the embryo source of the cell. Work in mice, reported last year by Robert Lanza, M.D., and his colleagues at Advanced Cell Technology, in Worcester, Mass., led to a similar finding of producing stem cells from a single human cell, called a blastomere, obtained from human embryos left over from attempts at in vitro fertilization as published in the August edition of Nature. The blastomere-derived stem cells produced neural cells. The findings suggest that stem cells for research and perhaps treatment could be produced using the cells that are routinely removed to check on embryos generated during in vitro fertilization. These particular experiments did not seek to preserve the embryos.

A Recipe to Revive Stem Cell Characteristics in More Mature Cells

Publishing in Cell, Japanese researchers show that a patient’s own cells might be able to turn back their developmental clocks and recapture the ability to act as stem cells, forming other cell types. The investigations led by Shinya Yamanaka, M.D., Ph.D., of Kyoto University showed that growing fibroblasts from adult mice in a culture medium containing four factors can reprogram the fibroblasts to become pluripotent; that is, to generate other types of cells. Fibroblasts are part of connective tissues such as skin and sinews. The factors are called Oct3/4, Sox2, c-Myc, and Klf4. This finding must be replicated by other laboratories, and the potential for forming tumors must be resolved, but the approach could provide an alternative to the use of embryos to generate stem cells for research and perhaps therapeutic purposes.
http://www.catfishchapter.org/news/Aug06Summary.html