Embargoed by Science for 2 p.m. EDT Thursday, October 2, 2003

It’s the Neighborhood that Matters in ALS, According to Medical Researchers

A multi-center effort led by researchers at the University of California, San Diego (UCSD) School of Medicine, has determined in mouse models of amyotrophic lateral sclerosis (ALS) that the nerve cells, or neurons, involved in ALS can be either damaged or saved from degeneration by neighboring non-neuronal cells.

The team reports that when non-neuronal cells harbor a genetic mutation associated with ALS, also called Lou Gehrig’s disease, they can cause damage in normal “motor neurons,” the long and complex nerve cells that control voluntary movement. Degeneration of motor neurons in ALS leads to progressive loss of muscle control, paralysis and ultimately death.

However, when the neighboring non-neuronal cells are normal, they can protect or rescue motor neurons from degeneration when the neurons themselves carry the ALS mutation. Published in the October 3, 2003 issue of the journal Science, the findings implicate non-neuronal cells in the disease, suggesting the potential of stem cell replacement therapy targeting non-neuronal cells as a treatment for ALS.

Don Cleveland, Ph.D.

Lawrence Goldstein, Ph.D.

“In place of the Herculean task of replacing the huge, meter-long motor neurons damaged by ALS, it would be easier to replace some of the surrounding cells with normal cells. Based on our findings, this could potentially prevent the degeneration and death of motor neurons that would otherwise be targeted for premature death,” said senior author Don Cleveland, Ph.D., UCSD Professor of Medicine, Neurosciences and Cellular and Molecular Medicine and member of the Ludwig Institute for Cancer Research.

Co-senior author Lawrence S.B. Goldstein, Ph.D., UCSD Professor of Cellular and Molecular Medicine and a Howard Hughes Medical Institute investigator, added that “we still need to do more research, but our hope is that stem cell therapy might be a candidate to rescue support cells and treat ALS patients.”

ALS is a progressive disease that attacks motor neurons that reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. Estimated to affect some 30,000 Americans, most people are diagnosed with ALS between the ages of 40 and 70, with 55 being the average age of diagnosis. Half of those diagnosed live only three to five years after diagnosis, while fewer than ten percent survive more than ten years.

To determine if ALS was caused directly by defects in the motor neurons themselves, or if other cells were inducing motor neurons to die, the researchers studied mouse models of ALS with a mutation in the gene superoxide dismutase (SOD1). The most common inherited form of ALS is caused by the SOD1 mutation.

The researchers developed 65 mice that were mixtures (chimeras) of normal cells and cells with the ALS-causing mutant SOD1 gene. Past studies have shown that mice consisting of 100 percent mutant SOD1 cells develop ALS. Those with normal SOD1 never get the disease. In the new study, many of the chimeric, or mixed-version, mice were completely disease free and most others developed ALS only at a later point in time (with extensions of average lifespan of between one and six months). Even in mice carrying the ALS mutation in all their motor neurons, those with a higher proportion of normal, or wild-type, non-neuronal cells had reduced motor neuron death.

The research team noted that the longer survival of mutant motor neurons surrounded by normal cells indicate that these healthy neighbor cells have a protective effect on the damaged neurons, slowing the progression of ALS even when the nerve cells carry the mutant gene. Conversely, the findings that mice with mutant non-neuronal cells develop symptoms of the disease even when the neuronal cells do not carry mutant SOD1 “supports the view that damage to adjacent non-neuronal cells by mutant SOD1 is a major contributor to disease.”

While the cause-and-effect of this relationship is not known, the researchers speculate that the non-neuronal cells play a vital role in nourishing the motor neurons, and scavenging toxins from the cellular environment of the motor neurons. When damaged with mutant SOD1, it appears that they fail in this role, contributing to the degeneration of the motor neurons.

The study was supported by grants from the National Institutes of Health, the Center for ALS Research at Johns Hopkins, the Canadian Institute of Health Research, the Angel Fund for ALS Research, Project ALS, and the Veterans Administration.

The study’s first author was A.M. Clement, Ph.D., Ludwig Institute for Cancer Research, and UCSD Departments of Cellular and Molecular Medicine and Neurosciences. Additional authors were M.D. Nguyen, M.D., Ph.D., and J.-P. Julien, Ph.D., Centre for Research in Neurosciences, Research Institute of the McGill University Health Care Centre, Montreal, Canada; E.A. Roberts, M.S., Howard Hughes Medical Institute and UCSD Department of Cellular and Molecular Medicine; M.L. Garcia, Ph.D. and S. Boillee, Ph.D., Ludwig Institute for Cancer Research, and UCSD Departments of Cellular and Molecular Medicine and Neurosciences; M. Rule B.S., and A.P. McMahon, Ph.D., Department of Molecular and Cellular Biology, Harvard University; W. Doucette, M.S. and R.H. Brown Jr., M.D., Day Neuromuscular Research Laboratory, Massachusetts General Hospital; and D. Siwek M.D. and R.J. Ferrante, Ph.D., Departments of Neurology, Pathology and Psychiatry, Boston University School of Medicine.

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UCSD Health Sciences Communications HealthBeat: http://health.ucsd.edu/news/

Don Cleveland's Lab page: http://cmm.ucsd.edu/Lab_Pages/cleveland/index.html

Larry Goldstein's Lab page: http://cmm.ucsd.edu/Lab_Pages/goldstein/index.html