Study sheds more light on Lou Gehrig’s disease mystery

X-ray crystal structures reveal negative traits of badly acting molecules

SAN ANTONIO (May 27, 2009) — Starved of a healthy diet of metals, abnormal molecules derived from families affected by Lou Gehrig’s disease start behaving badly, becoming unstable and clinging to each other.

Researchers from The University of Texas Health Science Center at San Antonio made those observations after examining new 3-dimensional images of the abnormal molecules. Their work, which was published online April 21 in the journal Biochemistry, may shed light on what causes the disease in one of its inherited forms.

“This is like a restaurant with no waiters – people who don’t get their food end up causing problems,” said lead author Duane Winkler, a UT Health Science Center graduate student who conducted the study in the X-ray crystallography laboratory of P. John Hart, Ph.D.

Immature superoxide dismutase 1 (SOD1) lacks copper, zinc and a disulfide bond, which lend stability to the molecule. Without these ingredients, the molecules become unruly and start sticking to each other. This causes the destructive knots of SOD1 seen at autopsy in cases of inherited Lou Gehrig’s disease, more formally called amyotrophic lateral sclerosis, or ALS.

More than 100 mutations are known to impair function of SOD1 molecules. The Health Science Center research specifically focused on mutations that prevent the molecule from interacting normally with a second molecule called CCS (short for copper chaperone for SOD1).

CCS is like a waiter serving up orders of copper and zinc. It is outnumbered 30-1 by its SOD1 patrons, so each “waiter” cruises from molecule to molecule, giving them the metals and the disulfide bonds they need.

“When CCS does this, it makes SOD1 very stable,” Winkler said. “But without the metals and the disulfide bond, SOD1 becomes unstable, sticks to other SOD1s or CCS itself, and causes disease.”

The Health Science Center team studied several SOD1 mutants, including one that lacks any ability to take in copper and zinc. The waiter “tries to put in the metals, but can’t, and never releases,” Winkler said.

Compounding the problem, there are no waiters available to serve new SOD1 molecules as they arrive. “So we have more molecules that contribute to the disease,” Winkler said.

Another mutation makes the SOD1 a moving target for its “waiter,” like a diner who keeps switching tables. “These mutants are so unstable that CCS doesn’t have time to get to them all before they stick together,” Winkler said.

“Duane’s work in determining X-ray structures of SOD1 mutants is innovative, and we think it goes a long way to characterizing the defects that cause ALS,” said Dr. Hart, who is the Ewing Halsell Foundation Endowed Professor in the Health Science Center Department of Biochemistry.

“What we’re saying is that the mutations prevent CCS from doing its job,” Dr. Hart said, “and that means you’ve got many metal-deficient molecules that are prone to aggregation. We now have a picture of what these SOD1 mutants look like.”

Lou Gehrig’s disease is a neurodegenerative disease. According to the ALS Association, 30,000 Americans – or roughly one in every 10,000 – have the disease. Among the 1.5 million people in Bexar County, an estimated 150 individuals have ALS. Two percent of ALS cases can be traced in families; the rest are of unknown cause.

The University of Texas Health Science Center at San Antonio is the leading research institution in South Texas and one of the major health sciences universities in the world. With an operating budget of $668 million, the Health Science Center is the chief catalyst for the $16.3 billion biosciences and health care sector in San Antonio’s economy. The Health Science Center has had an estimated $36 billion impact on the region since inception and has expanded to six campuses in San Antonio, Laredo, Harlingen and Edinburg. More than 25,600 graduates (physicians, dentists, nurses, scientists and other health professionals) serve in their fields, including many in Texas. Health Science Center faculty are international leaders in cancer, cardiovascular disease, diabetes, aging, stroke prevention, kidney disease, orthopaedics, research imaging, transplant surgery, psychiatry and clinical neurosciences, pain management, genetics, nursing, dentistry and many other fields. For more information, visit

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