- Scientists created human cellular models of familial and nonfamilial ALS, using cells taken from postmortem (after death) spinal tissue of people with ALS.
- They found that normally neuroprotective cells called astrocytes become toxic and caused nerve cells to degenerate in the new models for both the inherited and noninherited forms of the disease.
- It's known that astrocytes are toxic to motor neurons in a research mouse model of ALS that carries mutated SOD1 genes; now scientists have shown that astrocytes and the SOD1 protein appear to be similarly toxic in a model of noninherited ALS.
- The data warrant further study of the roles of both astrocytes and SOD1 protein in both familial and sporadic ALS.
Astrocytes — cells that normally support and protect nerve cells — have been found to cause motor neuron degeneration in newly created human cellular models of both inherited and noninherited ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease). Scientists tied the astrocytes' effects, in both forms of the disease, to the superoxide dismutase 1 (SOD1) protein.
Only about 5 to 10 percent of ALS cases are inherited, or familial; of those, approximately 20 percent are caused by mutations in SOD1. The majority of cases occur "sporadically," with no family history of the disease.
The findings implicate SOD1 protein and astrocytes in the death of muscle-controlling motor neurons in both SOD1-related familial and sporadic cases of ALS. Thus, targeting SOD1 in astrocytes may prove beneficial not only for people with SOD1-related familial ALS but also for those with some sporadic forms of the disease.
About the new findings
Previous studies in the SOD1 research mouse model, which overexpresses (overproduces) mutated SOD1 protein, have shown that astrocytes affected by mutant SOD1 are toxic to motor neurons. Until now, however, a lack of research models for sporadic ALS has prevented testing to determine whether astrocytes may be similarly toxic in the noninherited form of the disease.
The research team first created a new research model of ALS, generating astrocytes from cells retrieved from postmortem (after death) spinal cord tissue. Samples were taken from one person with SOD1-related familial ALS and seven people with the sporadic form of the disease. The team then cultured (grew) the astrocytes in combination with mouse motor neurons.
- After one day, the number of motor neurons was approximately the same in all samples, whether cultured with ALS-related astrocytes or non-ALS (control) astrocytes.
- After four days, motor neurons that were paired with familial SOD1-related ALS astrocytes began to degenerate, and after five days they numbered only half that of motor neurons grown with non-ALS astrocytes (control group).
- Motor neurons paired with sporadic-ALS astrocytes also began to degenerate at four days. After five days, there were 45 to 70 percent fewer motor neurons in this group than in the non-ALS astrocyte control group.
The investigators noted that the motor neuron damage caused by astrocytes derived from the person with familial ALS and those with sporadic ALS was "indistinguishable," indicating a "shared mechanism for motor neuron death."
The team then demonstrated that toxic effects could be reversed by "knocking down," or causing a decrease, in SOD1 protein levels in astrocytes derived from either the familial or sporadic ALS cells. Suppression of SOD1 by approximately 50 percent in the sporadic ALS astrocytes was enough to protect motor neurons.
The investigators published their findings online Aug. 10, 2011, in Nature Biotechnology. (See Astrocytes from familial and sporadic ALS patients are toxic to motor neurons.)
Team members of the National Institutes of Health-supported study included several scientists who previously have received MDA research grants for ALS-related work: Brian Kaspar and Arthur Burghes, both at Ohio State University in Columbus, Ohio; and Jerry R. Mendell, director of the neuromuscular research program at Nationwide Children's Hospital in Columbus, Ohio.
Astrocytes are nervous system support cells that normally protect motor neurons. But a growing body of evidence indicates that in ALS the star-shaped cells may cause motor neurons to die. (See ALS: Not Just About Motor Neurons Anymore, MDA/ALS Newsmagazine, May 2010, and Is Fixing Motor Neurons the Only Path to Treating ALS?, MDA/ALS Newsmagazine, February 2009.)
The current study links the SOD1 protein to astrocyte-associated toxicity, and supports the theory that knocking down SOD1 may help motor neurons survive longer.
MDA-supported scientists have been researching ways to do just that.
MDA supported early-stage research by neuroscientist Don Cleveland at the University of California, San Diego School of Medicine in La Jolla that demonstrated that compounds called antisense oligonucleotides — synthesized chemical agents sometimes called antisense, oligos, or simply AONs — can reach motor neurons and support cells in the central nervous system.
Since 2007, MDA has supported neurologist Timothy Miller at Washington University in St. Louis to work with Isis Pharmaceuticals of Carlsbad, Calif., on the development and testing of an experimental antisense therapy specifically targeted at mutant SOD1.
Human trials began in March 2010 of the experimental antisense therapy ISIS-SOD1-Rx, a compound designed to block production of toxic SOD1 protein in people with the SOD1-related form of familial ALS.
Preliminary results from the phase 1 trial so far have been favorable, and a phase 2 trial of ISIS-SOD1-Rx already is in the planning stages. MDA grantee James Berry at Massachusetts General Hospital in Boston is a member of the study team planning the trial.
In another research endeavor, MDA grantee François Berthod, a professor in the department of surgery at Laval University in Quebec City, Canada, is using a tissue-engineered spinal cord model to study the interactions of different nervous system cell types, including motor neurons and astrocytes, as a means of determining the conditions that contribute to motor neuron death in ALS.
Meaning for people with ALS
The new findings help strengthen the hypothesis that astrocyte-mediated toxicity is one possible mechanism underlying motor neuron death in ALS.
The newly discovered similarity between astrocyte toxicity in an SOD1-associated familial ALS model and in models of sporadic ALS should help improve understanding of the disease and pinpoint targets for therapy development.
Importantly, results from this study indicate that potential benefits gained by knocking down SOD1 may be applicable to a far greater number of people with the disease than previously thought.
Also of note, the new "patient-specific" human cellular models created by the investigators are expected to be useful in the study of both familial and sporadic ALS.
"We've created a new set of tools to study the disease — patient-specific cells," Kaspar said. "This is going to open up a lot of new doors in understanding the disease and testing new therapeutics."