Sticky mutant proteins implicated in Lou Gehrig...( Bethesda MD A new study indicates tha...)

Bethesda, MD A new study indicates that mutant Cu/Zn superoxide dismutase (SOD1) enzymes that are associated with an inherited form of Lou Gehrig's disease cause the protein to become sticky in tissues. Partial unfolding of the mutant protein can expose hydrophobic residues that may promote abnormal interactions with other proteins or membranes in the cell.

The research appears as the "Paper of the Week" in the August 19 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

Over 5,600 people in the U.S. are diagnosed with amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease each year. About 30,000 Americans have the disease at any given time, and 10% of cases are inherited.

"Amyotrophic lateral sclerosis is a neurodegenerative disorder in which neurons of the motor pathways in the brain and spinal cord die," explains Dr. Lawrence J. Hayward of the University of Massachusetts Medical School. "It typically strikes during middle age, and although it may start with only mild weakness, the symptoms can spread insidiously over months to impair mobility, speech and swallowing, and ultimately the muscles required for respiration."

Despite the prevalence of ALS, the biological mechanisms that kill the motor neurons in most patients are incompletely understood. However, for a fraction of inherited ALS patients, mutations in the gene for SOD1 cause the disease by creating a toxic enzyme. Evidence suggests that misfolding or partial unfolding of mutant SOD1 proteins in these patients might be key to the toxicity.

Hoping to learn more about how SOD1 contributes to ALS, Dr. Hayward began to study the properties of several ALS-causing SOD1 mutants in research sponsored by the National Institutes of Health and the ALS Association.

"Our efforts have focused upon trying to explain how over 100 different mutant forms of SOD1 cause inherited ALS," says Dr. Hayward. "The
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Contact: Nicole Kresge
nkresge@asbmb.org
301-634-7415
American Society for Biochemistry and Molecular Biology
10-Aug-2005

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