Scientists think they have found a way to prevent and possibly reverse the most debilitating symptoms of the rare, progressive childhood degenerative disease called ataxia-telangiectasia, or A-T disease, that leaves children with slurred speech, unable to walk, and in a wheelchair before they reach adolescence.
Neurological degeneration is not the only life-threatening effect associated with A-T disease. It occurs in an estimated 1 in 40,000 births and also causes the immune system to break down and leaves children extremely susceptible to cancers such as leukemia or lymphoma. There is no known cure and most die in their teens or early 20s. According to the AT Children's Project, many of those who die at a young age might not have been properly diagnosed so it may be more common.
Karl Herrup, chair of the Department of Cell Biology and Neuroscience at Rutgers outlined new information on why this genetic disease attacks the cerebellum, a part of the brain that controls movement coordination, equilibrium, and muscle tone, and other regions of the brain.
Using mouse and human brain tissue studies, Herrup and colleagues found that in the brain tissue of young adults who died from A-T disease, a protein known as HDAC4 was in the wrong place. HDAC4 is known to regulate bone and muscle development, but it is also found in the nerve cells of the brain. The protein that is defective in A-T, they discovered, plays a critical role in keeping HDAC4 from ending up in the nucleus of the nerve cell instead of in the cytoplasm where it belongs. In a properly working nerve cell, the HDAC4 in the cytoplasm helps to prevent nerve cell degeneration; however, in the brain tissue of young adults who had died from A-T disease, the protein was in the nucleus where it attacked the histones – the small proteins that coat and protect the DNA.
"What we have found is a double-edged sword," said Herrup. "While the HDAC4 protein protected a neuron's function when it was in the cytoplasm, it was lethal in the nucleus."
To prove this point, Rutgers scientists analyzed mice, genetically engineered with the defective protein found in children with A-T, as well as wild mice. The animals were tested on a rotating rod to measure their motor coordination. While the normal mice were able to stay on the rod without any problems for five to six minutes, the mutant mice fell off within 15 to 20 seconds.
After being treated with trichostation A (TSA), a chemical compound that inhibits the ability of HDAC4 to modify proteins, they found that the mutant mice were able to stay on the rotating rod without falling off – almost as long as the normal mice.
Although the behavioral symptoms and brain cell loss in the engineered mice are not as severe as in humans, all of the biochemical signs of cell stress were reversed and the motor skills improved dramatically in the mice treated with TSA. This outcome proves that brain cell function could be restored, Herrup said.
"The caveat here is that we have fixed a mouse brain with less devastation and fewer problems than seen in a child with A-T disease," said Herrup. "But what this mouse data says is that we can take existing cells that are on their way to death and restore their function."
Herrup says although this discovery does not address all of the related medical conditions associated with the disease, saving existing brain cells – even those that are close to death – and restoring life-altering neurological functions would make a tremendous improvement in the lives of these children.
"We can never replace cells that are lost," said Herrup. "But what these mouse studies indicate is that we can take the cells that remain in the brains of these children and make them work better. This could improve the quality of life for these kids by unimaginable amounts."
Additionally, Herrup says, the research might provide insight into other neurodegenerative diseases. "If this is found to be true, then the work we've done on this rare disease of childhood may have a much wider application in helping to treat other diseases of the nervous system, even those that affect the elderly, like Alzheimer's," he said.
Published in Nature Medicine.
(edited to correct misspelling of the disease name)
- PHYSICAL SCIENCES
- EARTH SCIENCES
- LIFE SCIENCES
- SOCIAL SCIENCES
Subscribe to the newsletter
Stay in touch with the scientific world!
Know Science And Want To Write?
- Single Top Production At The LHC
- Our Ethical Responsibilities To Baby Terraformed Worlds - Like Parents
- Higher Potency Cannabis Linked To Brain White Matter Damage
- Study: Paying For Transgender Health Care Cost-effective
- Dietary Restriction, Circadian Rhythm, And Long Life
- New Metric Mapping Top 10 European Heat Waves Predicts Strong Increase In Next 2 Decades
- Supersymmetry Is About To Be Discovered, Kane Says
- "If you like this article, any of you, you might be interested in my Vanishing Metronome Click..."
- "Usually this type of criticism is based on the idea that the way to use a metronome is to play..."
- "No, it's just a work of fiction. Either a hoax, or writings by over-imaginative people who have..."
- "See also Who owns space? US asteroid-mining act is dangerous and potentially illegal..."
- "Metronomes - Do You Need Them? If you're musician and want to ignore your inner self, conforming..."
- Earth's first ecosystems were more complex than previously thought, study finds
- Soil pulled from deep under Oregon's unglaciated Coast Range unveils frosty past climate
- Mystery of how snakes lost their legs solved by reptile fossil
- Seizure risk of anti-shivering agent meperidine greatly overstated
- Immune-disorder treatment in mice holds potential for multiple sclerosis patients