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Anson Pierce, Ph.D., said the damage might be a common contributing factor to ALS cases.
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SAN ANTONIO (Oct. 13, 2008) — In the past two decades, great strides have been made to explain the genetic basis of inherited amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. Defects in a gene called SOD1 are now firmly linked to a type of ALS that is passed down through families.

But SOD1-related cases represent only 2 percent of all ALS patients. Researchers continue to seek other factors that contribute to the great majority of cases of this neurodegenerative, muscle-wasting disease.

Now, from laboratories of the Barshop Institute at The University of Texas Health Science Center at San Antonio and labs at the South Texas Veterans Health Care System, comes a study* that suggests there may be a common fingerprint in different types of ALS. The research is detailed in the Oct. 24 issue of the Journal of Molecular Biology.

Sticky proteins
Using a new technology to rapidly screen hundreds of thousands of proteins in living cells for structural changes, the scientists found damage to a protein called GAPDH in ALS mouse models. ALS may be triggering oxidative stress — the aging of cells that makes them more vulnerable to disease. The oxidative stress may be reshaping the GAPDH, making it less functional.

The changes make the proteins’ coats sticky so that they clump together. The researchers studied this stickiness in skeletal muscle tissues from two ALS mouse models — one that exhibits greater oxidative stress, rapid disease progression and a shorter lifespan, and a second that shows less oxidative stress, slower worsening of disease and a longer lifespan. Both mouse models have SOD1 mutations.

GAPDH activity was diminished by 50 percent in the severe ALS mouse model and was 22 percent diminished in the milder ALS model. The groups’ relative impairment matched well with their rates of oxidative stress, disease progression and longevity.

Potential common link
“In both of these mouse models, which are fairly different from each other, we found the same protein getting damaged,” lead author Anson Pierce, Ph.D., said. “This identifies a general theme that may be going on in all ALS patients.”

Dr. Pierce is a U.S. Department of Veterans Affairs grant recipient, a Barshop Institute member and a postdoctoral fellow in the Health Science Center Department of Cellular and Structural Biology.

Asish Chaudhuri, Ph.D., said locating stickiness on the molecule might make it possible to circumvent the damage.

“The exciting part is we have identified a region on the molecule that is profoundly affected. Perhaps we can design ways to circumvent the damage,” said the senior author, Asish Chaudhuri, Ph.D., assistant professor of biochemistry, Barshop Institute member and VA grant recipient. He has worked extensively with the new screening system, which the late Paul Horowitz, Ph.D., a Health Science Center biochemist, developed.

Protein clumps have been found in ALS animal models during autopsies, but it has never been possible to document structural changes earlier in the disease process, Dr. Chaudhuri noted.

Oxygen’s role
Oxidative stress in the animals correlated strongly with the GAPDH damage.

“For years scientists believed oxidative stress from a disease process could reshape proteins to be less functional,” said Arlan G. Richardson, Ph.D., Barshop Institute director, professor of cellular and structural biology and senior career research scientist with the VA. “We believe we are seeing those effects now on an ALS-related protein in living tissue.”

Human ALS patients also exhibit signs of oxidative stress, but it is not known whether this is consistent in all ALS patients, Dr. Pierce said.

* GAPDH Is Conformationally and Functionally Altered in Association with Oxidative Stress in Mouse Models of Amyotrophic Lateral Sclerosis, Journal of Molecular Biology, Volume 382, Issue 5, 24 October 2008, Pages 1195-1210; Anson Pierce, Hamid Mirzaei, Florian Muller, Eric De Waal, Alexander B. Taylor, Shanique Leonard, Holly Van Remmen, Fred Regnier, Arlan Richardson, Asish Chaudhuri

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