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Filaments in crystals reveal ALS's destructive work

San Antonio (May 19, 2003) — A research team from The University of Texas Health Science Center at San Antonio (UTHSC), in conjunction with colleagues in California, Massachusetts and England, has discovered subtle but deadly differences in the shape of protein structures that are mutated in familial amyotrophic lateral sclerosis (ALS), the inherited form of Lou Gehrig's disease. The scientists' paper, which includes 3-D X-ray crystal pictures of the mutant proteins, is to appear in the June 2003 issue of Nature Structural Biology.

The abnormal proteins reach out and touch each other, something their healthy counterparts don't do. The mutant proteins clump to form filaments that are potentially damaging to motor neurons.

"A protein called superoxide dismutase (SOD1) is known to be mutated in familial ALS," said lead author P. John Hart, Ph.D., assistant professor of biochemistry and director of UTHSC's X-ray Crystallography Core Laboratory. "Our paper shows how several mutant SOD1 proteins form two types of larger filamentous structures (both linear and helical) while the normal SOD1 protein does not." It is widely believed that such assemblies, or aggregates, of mutant SOD1 somehow eventually kill the motor neurons. When the motor neurons die, the affected individual is left paralyzed.

Scientists noticed SOD1 in the aggregates of diseased motor neurons several years ago. As illustrated in the new research, mutations cause the proteins to have a slightly different molecular shape than normal, resulting in different biochemical properties. "Now that we know the proteins are touching each other inappropriately, we can begin to think about developing compounds that will cling to the mutant proteins and prevent it from happening," Dr. Hart said. "Admittedly, that is in the future."

Researchers from the Health Science Center, the CCLRC Daresbury Laboratory in England, the University of California at Los Angeles and the University of Massachusetts Medical School collaborated on the study.

ALS affects about 1 in 1,000 people. Ten percent of cases are called "familial" because they can be associated with heredity; the other 90 percent are called "sporadic" because they do not appear to be linked to inheritance. "About 2 percent to 5 percent of ALS cases are attributed to mutations in the SOD1 protein," Dr. Hart said. "The hope and the belief is that understanding the inherited form of ALS will also help us understand sporadic cases."

Bill Erwin, a 57-year-old Austin, Texas, resident who travels to the Health Science Center to see ALS specialist Carlayne Jackson, M.D., certainly hopes so. His case of ALS is not linked to family history. A 25-year software development manager with the ARAMCO oil company in Saudi Arabia, he began having symptoms in 2000 and was diagnosed in March 2001 at the Mayo Clinic in Scottsdale, Ariz. Mayo physicians referred him to Dr. Jackson. "I'm very fortunate in that I have a slow-progressing form," Erwin said. "I can still walk a little bit, my arms are fine and my breathing is good. I use a powered wheelchair most of the time." Now retired, he enjoys playing bridge with buddies. Erwin was an intercollegiate bridge champion of Texas while a student at UT Austin in the 1960s. "I used to be a big tennis player, but had to shelve my overhead due to ALS," he said.

Dr. Hart's finding is meaningful to patients because "we live in hope," Erwin said. "It's encouraging that people are looking at ALS because, through great research or serendipity, they may discover something to help me and other patients with ALS."

"Dr. Hart's study is important because it provides experimental evidence as to how a disease process such as ALS can be explained at the molecular level," said Merle S. Olson, Ph.D., dean of the Graduate School of Biomedical Sciences at the Health Science Center. "He has shown quite clearly how the SOD1 protein expressed from ALS patients differs in its aggregation or polymerization properties from the same protein from normal individuals."

"This study is the first to show evidence in vitro [in the laboratory] how SOD1 aggregates may be formed in vivo [in the body]," said Lucie Bruijn, Ph.D., science director and vice president of the ALS Association. "The presence of aggregated proteins in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's and ALS is an emerging common theme. Whether these aggregates are key players in causing toxicity and cell death remains unresolved." Dr. Hart's findings, she added, "may lead to an understanding of how to disrupt aggregate formation and, should aggregates be integral to the disease mechanism, may lead to potential therapeutic approaches."

Dr. Olson said this finding and others may provide "a 'unifying principle' in our understanding as to how a single change in the amino acid sequence of a protein can lead to changes in the structural properties of proteins and then the pathological indications seen in ALS patients. In this sense, Dr. Hart's observation is a seminal finding if the aberrant molecular structure induced by the genetic alteration can explain the physiological dysfunction observed in the disease."

Co-authors are Jennifer Stine Elam and Alexander B. Taylor of the Health Science Center, Richard Strange, Svetlana Antonyuk and S. Samar Hasnain of the CCLRC Daresbury Laboratory, Peter A. Doucette, Jorge A. Rodriguez, Joan Selverstone Valentine and Todd O. Yeates of UCLA, and Lawrence J. Hayward of the University of Massachusetts Medical School.

The ALS Association and the National Institute of Neurological Disorders and Stroke provided funding for this study.

Contact: Will Sansom