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Leveling the Playing Field

Health Science Center team first to show how Lou Gehrigís disease can be explained at molecular level

August 2003

by Will Sansom

Tucked away in the laboratory of John Hart, Ph.D., is a picture of a man and his family. The husband-father in the photo was a victim of amyotrophic lateral sclerosis (ALS), the same neurodegenerative disorder that toppled baseball slugger Lou Gehrig. The man, who died before Dr. Hart joined the department of biochemistry in 1998, serves as a reminder of the human tragedy of ALS. Fortunately, the work performed in Dr. Hartís laboratory is viewed as foundational to finding a therapy for this paralyzing killer.

ALS causes atrophy of the motor neurons in the spinal cord and brain, loss of muscle control, and death within two to five years of onset of symptoms. According to The ALS Association, more than 30,000 Americans have the disease and nearly 6,000 new cases are diagnosed each year nationwide. But hope began to spring up for patients a decade ago, when scientists linked the first gene to ALS. This gene contains the blueprints to make the protein copper-zinc superoxide dismutase (abbreviated SOD1). SOD1 anomalies account for up to one-fifth of inherited ALS cases and possibly up to 3 percent of cases in people with no family history of ALS.

Scientists have since discovered more than 90 different errors in mutated copies of the SOD1 gene and have noted abnormal "clumps" containing SOD1 on the motor neurons of patients with inherited ALS. It is theorized that these clumps disrupt important functions that ordinarily prevent cell death.

  SOD1 proteins
In Lou Gehrigís disease, SOD1 proteins Ďreach out and touch each other,í something their healthy counterparts donít do.
This summer, Dr. Hartís team reported the first evidence suggesting how the clumps form. "No one has ever demonstrated at the molecular level how ALS mutations might lead to disease," he said. "Our paper shows how several mutant SOD1 proteins form two types of larger structures while the normal SOD1 protein does not." One structure is long and slender like the filament in a light bulb; the other is a helical tube that Dr. Hart believes is a precursor to the clump formation. The team employed x-ray crystallography, an imaging technique that produces 3-D pictures of molecular structure, to examine the difference between healthy and aberrant SOD1.

The abnormal proteins reach out and touch each other, something their healthy counterparts donít do. They apparently touch because the gene mutations cause them to lose their copper and zinc atoms, giving them just the right shape and charge to lock on to each other. "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.

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. "The hope and the belief is that understanding the inherited form of ALS will also help us understand sporadic cases," Dr. Hart said.

Bill Erwin, an Austin 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. "Iím 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."

Dr. Hartís finding is meaningful to patients because "we live in hope," Erwin said. "Itís 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. Hartís 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 the laboratory how SOD1 aggregates may be formed 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 Alzheimerís, Parkinsonís, Huntingtonís and ALS is an emerging common theme."

Jill Heemskerk, Ph.D., of the National Institute of Neurological Disorders and Stroke (NINDS), said it has been difficult to link aggregate theory with ALS because the clumps seen in Lou Gehrigís are less dramatic than those seen in Alzheimerís and other neurodegenerative diseases. This finding "helps tie ALS into a larger world," she said.

Mary L. Klenke, patient services coordinator with The ALS Associationís South Texas Chapter, presented the photo of the man and his family to Dr. Hart five years ago. She said his research team has kept the South Texas Chapter well informed on the latest findings. "Dr. Hartísenthusiasm in striving to find the answers to ALS gives all people living with this disease and their families a reason for hope," Klenke said.

Co-authors included Jennifer Stine Elam and Alexander B. Taylor of the Health Science Center. The ALS Association and the NINDS provided funding for this study, which was reported in the June issue of Nature Structural Biology.

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