Finding Suggests New Therapy For Genetic Disorder
La Jolla, CA – A home movie of toddlers will show them wobble and weave, often to the amusement of adult viewers. But for babies born with the rare genetic disease ataxia-telangiectasia, commonly known as A-T, what may seem like normal and adorable lack of polish accelerates into a progressive and pervasive loss of muscle control and early death.
By locating the source of neurodegeneration, a new Salk study suggests a course of potential treatment, bringing hope to those afflicted by this currently incurable disease.
"The exciting thing here is that there are therapies available that now make sense to try," said Brad Margus, president of the A-T Children's Project, a patient advocacy group for patients with A-T. Ataxia refers to the altered gait produced by the neurodegenerative effects of the disease; telangiectasia refers to patches of dilated blood vessels commonly seen in patients' skin.
Babies born with A-T appear perfectly normal and healthy for their first several years. As toddlers or young schoolchildren they show their first symptoms, typically by beginning to sway. "The seriousness of the condition is not immediately clear," said Salk Assistant Professor Carrolee Barlow, M.D., lead author of the study, which appears in the current issue of the Proceedings of the National Academy of Sciences. "But by their teen years, most are in wheelchairs, and many lose control of their eye movements, so even reading or focusing on a game becomes difficult."
A-T patients are also prone to cancers, usually leukemias and lymphomas, and lack a robust immune system. Before the age of 30, most succumb to either cancer or infection.
With colleagues at the National Institutes of Health, Barlow developed mice that lacked the gene Atm, shown in 1995 to be the cause of A-T. The mice display symptoms closely paralleling the course of the human disease.
"Developing an animal model for the disease provided the breakthrough we needed to find the underlying defect, an inability to cope with oxidative damage," said Barlow.
In the current study, Barlow and collaborators examined brain cells from the cerebellums of these mice, the part of the brain known to be affected by A-T.
"The cerebellum is the central control panel for all movements," said Barlow. "For instance, if you hold your arm out to your side and decide to lift it over head, your cerebellum informs the rest of your brain and body about where your arm is and in which direction it should be moved."
In A-T patients, important cells in the cerebellum, called Purkinje cells, slowly but steadily die off, causing the progressive loss of motor control. When Barlow and colleagues looked at the Purkinje cells in the Atm-deficient mice, they found the likely killer.
"The cells showed clear evidence of oxidative damage," said Barlow. "We all encounter oxidants, commonly called free radicals, in our day-to-day lives – they're byproducts of ordinary metabolism. Most of us can contain or repair the insults these toxins inflict on our cells, but in people with A-T, the defense system appears to be impaired in these important brain cells."
Oxidants are highly reactive compounds that wreak havoc with the sensitive chemical balance inside cells, creating "molecular debris." Inside the brain cells of Atm -deficient mice, Barlow and colleagues found telltale scars of oxidative assault.
The results were somewhat unexpected, since the product of the Atm gene is not an enzyme specialized to cope with oxidative stress. Rather, it is a kinase, a type of protein that typically switches other proteins on and off.
"So we think the ATM protein most likely turns on defense system molecules," said Barlow. "When it's missing, oxidative damage builds up inside these brain cells, until key enzymes and other proteins no longer function and the cells die. This type of cumulative effect is seen in other neurodegenerative disorders and, in fact, one school of thought states that normal aging is due to an accumulation of oxidative damage."
She noted an intriguing similarity between the Atm gene and a gene called age-1, found in the tiny experimental worm Caenorhabditis elegans. Worms that manufacture extra age-1 live much longer than their counterparts.
"The worm findings underscore the central role of oxidative defense in maintaining life," said Barlow. "They also suggest that it may be possible to prolong life by administering anti-oxidant medications. Vitamin E is one anti-oxidant found in our diets, and there are other more potent drugs that could be tried to prolong the lives of people with A-T."
Said Margus: "Dr. Barlow's study is the first to present hard empirical evidence of what is actually causing brain cells to die in this disease. And that gives us a rationale for potential treatment."
The oxidative defense defect may also help to explain the high cancer rate seen in A-T patients, since damage to DNA can result in the types of mutations that give rise to cancer cells.
Collaborators on the study include Phyllis A. Dennery at Stanford University, Mark K. Shigenaga at the University of California, Berkeley, Mark A. Smith at Case Western Reserve University, Jason D. Morrow and L. Jackson Roberts II at Vanderbilt University, Anthony Wynshaw-Boris at the University of California, San Diego and Rodney L. Levine at the National Heart, Lung, and Blood Institute. The study, titled "Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs" was supported by the National Institutes of Health, the Burroughs Wellcome Fund, and the A-T Children's Project. Barlow holds the Frederick B. Rentschler Developmental Chair.
Brad Margus can be reached at (800) 543-5728. The A-T Children's Project can assist in arranging patient interviews: (561) 395-2621.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.