(Press-News.org) HOUSTON -- (May 30, 2013) – In some neurodegenerative diseases, and specifically in a devastating inherited condition called spinocerebellar ataxia 1 (SCA1), the answer may not be an "all-or-nothing," said a collaboration of researchers from Baylor College of Medicine, the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and the University of Minnesota in a report that appears online in the journal Nature. The problem might be solved with just a little less.
"If you can only decrease the levels of ataxin-1 (the protein involved in SCA1) by 20 percent, you can reduce many symptoms of the disease," said Dr. Huda Zoghbi, professor of molecular and human genetics and pediatrics at BCM and director of the Neurological Research Institute. She is also a Howard Hughes Medical Institute Investigator.
Her long-time colleague Dr. Harry Orr, director of the University of Minnesota Institute for Translational Neuroscience, echoed that sentiment: "Perhaps, if you decrease the levels of the protein, you will decrease the severity of the disease." In this report, the laboratories of Zoghbi, Dr. Juan Botas, also of BCM and the Neurological Researcher Institute, Dr. Thomas Westbrook, assistant professor of molecular and human genetics at BCM, and Orr identified a molecular pathway in the cell (RAS/MAPK/MSK1) with components that can be modulated slightly to reduce the levels of defective ataxin-1, the protein that causes disease in patients with the disorder.
Spinocerebellar ataxia 1 occurs when the ataxin-1 gene is mutated, with three letters of the DNA alphabet repeating many, many times. The abnormal protein that results cannot fold correctly and piles up in the cell, eventually killing it. As with many neurodegenerative disorders, the process can take over a decade. A person usually does not develop symptoms of this form of ataxia until he or she is 30 years old or older. The person develops gait problems, eventually loses the ability to speak and function and dies. Zoghbi and Orr teamed to find the gene associated with the disorder in 1993. Their work on the disease has spanned 20 years.
Totally eliminating the protein would not work. Mice that lack the gene have problems with learning and memory, indicating that ataxin-1 plays a role in those activities. Reducing the levels of ataxin-1 does not cure the disease, but it can significantly delay onset.
A Collaborative Innovation Award from the Howard Hughes Medical Institute enabled Zoghbi to put together the team that could screen for the genes or the gene pathway that could be manipulated to result in less ataxin-1.
"Harry and I had studied the disease and we had animal models. Botas, professor of molecular and human genetics at BCM, had a fruit fly model and Dr. Westbrook had a nice technology that enabled us to monitor ataxin-1 levels."
They began with a screen for genes that could affect the levels of ataxin-1 produced in the cell, said Dr. Ismail Al-Ramahi, a postdoctoral fellow in the lab of Botas. Dr. Jeehye Park, a post-doctoral fellow in Zoghbi's laboratory, and Al-Ramahi are co-first authors of the report. Park and her colleagues carried out the screen in human cell lines and Al-Ramahi and his colleagues carried out the screen in fruit flies (Drosophila melanogaster).
The screen in human cells focused on forms of enzymes called kinases because they are susceptible to the effects of drugs. Using a special technique called RNA silencing, they targeted each known human kinase. At the same, Botas and Al-Ramahi screened kinase genes in fruit flies with a form of SCA1. When the two laboratories compared results, they found 10 genes in common that when inhibited could reduce the levels of ataxin-1 as well as the toxicity associated with it. The genes were part of the RAS/MAPK/MSKI signaling cascade within the cell.
Then the researchers focused on one protein in this pathway called MSK1 and found that when its levels were decreased in mice that were laboratory models of SCA1, the levels of ataxin-1 dropped and the animals improved. That was the final experiment that proved that reducing levels of the protein could stave off the disease.
"We want to look for more pathways," said Zoghbi. If they find more pathways, they may be able to reduce toxicity. "If you have a pain and you take acetaminophen all the time, you have a risk of toxicity. Similarly, if you took a nonsteroidal anti-inflammatory all the time, you would have another toxicity. If you alternate between them, there is less toxicity. If we hit only one pathway with a big inhibition, we risk some toxicity. If we find two or three pathways and hit each only a little, the rest of the body should not be hurt. Each little hit should help us reduce ataxin-1 by a respectable amount."
"I think what is novel about this paper is the integration of the screen in cells that was done in Huda's lab and the screen in fruit flies done in our lab to look for targets for genes about which we knew nothing ahead of time," said Botas.
While the finding in spinocerebellar ataxia 1 is exciting, its potential application in other diseases is even more provocative.
"Now that we know that it works with ataxin-1, we can revisit many proteins whose levels drive neurodegeneration in sporadic and inherited diseases such as Alzheimer's, Parkinson's, Huntington's and other neurological disorders," said Zoghbi. "This is a pilot study and the results from it are as important as a new pathway in neurodegenerative disease research."
"These are diseases that take a long time to develop," said Park. "Most Alzheimer's occurs after the age of 85. If we could delay it until age 95, that would be very helpful."
"This is getting us really close, not only for SCA1, but I think it's going to be a guidepost for work on a lot of other neurodegenerative diseases," said Orr. "It sets us a beautiful research strategy to get at that goal."
###
Others who took part in this work include Qiumin Tan, Javier R. Diaz-Garcia, Tatiana Gallego-Flores, Hsiang-Chih Lu, Hyojin Kang, Yoontae Lee, Paymaan Jafar-Nejad, Layal S. Sayegh, Ronald Richman, Xiuyun Liu, Yan Gao, and Chad A. Shaw, all of BCM, Nissa Mollema, Sarita Lagalwar and Lisa Duvick of the University of Minnesota and J. Simon C. Arthur of the MRC Protein Phosphorylation Unit, School of Life Science at the University of Dundee in the United Kingdom.
Funding for this work came from the Howard Hughes Medical Institute Collaborative Innovation Award.
END
UCLA research has shown that that children with attention-deficit hyperactivity disorder are far more likely than other kids to develop serious substance abuse problems as adolescents and adults. But do stimulant medications used to treat ADHD contribute to the risk?
UCLA psychologists have conducted the most comprehensive assessment ever on this question and have found that children with ADHD who take medications such as Ritalin and Adderall are at no greater risk of using alcohol, marijuana, nicotine or cocaine later in life than kids with ADHD who don't take these ...
During the last ice age, when thick ice covered the Arctic, many scientists assumed that the deep currents below that feed the North Atlantic Ocean and help drive global ocean currents slowed or even stopped. But in a new study in Nature, researchers show that the deep Arctic Ocean has been churning briskly for the last 35,000 years, through the chill of the last ice age and warmth of modern times, suggesting that at least one arm of the system of global ocean currents that move heat around the planet has behaved similarly under vastly different climates.
"The Arctic ...
Charles H. Hennekens, MD, DrPH, the first Sir Richard Doll professor and senior academic advisor to the dean in the Charles E. Schmidt College of Medicine at Florida Atlantic University has published in the current issue of the Lancet the most comprehensive analyses of the benefits and risks of non-steroidal anti-inflammatory drugs (NSAIDs), which include cyclo-oxygenase-2 inhibitors (coxibs).
Hennekens and colleagues from around the world, under the direction of the Clinical Trial Service and Epidemiology Studies Unit at the University of Oxford, conducted a world-wide ...
Researchers at Griffith University's Centre for Quantum Dynamics have demonstrated that, contrary to what the Heisenberg uncertainty relation may suggest, particle properties such as position and momentum can be measured simultaneously with high precision.
But it comes at a cost.
The findings have been published in Experimental Test of Universal Complementarity Relations in the prestigious journal Physical Review Letters.
Co-author Dr Michael Hall said the work represents an important advance in the quantitative understanding and experimental verification of complementarity; ...
It is a commonly held perception that getting in shape and staying there requires hard work and hours upon hours of training. New research shows the opposite – it seems that only four minutes of vigorous activity three times per week is enough to be fit and healthy.
Regular training improves maximal oxygen uptake (VO2max), which is a well-established measure of physical fitness. However, just how much exercise, and how intense that exercise should be to deliver the biggest benefit remains to be defined. Now, researchers from the KG Jebsen – Centre of Exercise in Medicine ...
PITTSBURGH, May 30, 2013– Medical emergencies during commercial airline travel can be a frightening experience, but most situations are well-treated by other passengers and flight attendants, in collaboration with consulting physicians on the ground. A University of Pittsburgh study published today in the New England Journal of Medicine found that doctors, nurses and other medical professionals on the aircraft helped to treat sick fellow passengers in three-fourths of the emergencies studied.
Led by Christian Martin-Gill, M.D., M.P.H., assistant professor of emergency ...
In one of the first successful attempts at genetically engineering mosquitoes, Howard Hughes Medical Institute (HHMI) researchers have altered the way the insects respond to odors, including the smell of humans and the insect repellant DEET. The research not only demonstrates that mosquitoes can be genetically manipulated using the latest research techniques, but paves the way to understanding why the insect is so attracted to humans, and how to block that attraction.
"The time has come now to do genetics in these important disease-vector insects. I think our new work ...
Researchers from Northeastern University are among the many scientists helping NASA use the weightlessness of space to design stronger materials here on Earth.
Structural alloys might not sound familiar, but they are an integral part of everyday materials, such as aircraft wings, car bodies, engine blocks, or gas pipelines. These materials are produced through solidification—a process similar to the making of ice cubes. "Solidification happens all around us, either naturally, as during the crystallization of familiar snow-flakes in the atmosphere, or in technological ...
CORVALLIS, Ore. – Researchers at Oregon State University have helped develop new environmental monitoring technology that will allow farmers thousands of miles away, in west and central Asia, to save millions of dollars while more effectively combatting a pest that is threatening their wheat crops.
Twenty million acres of wheat in parts of Asia and North Africa are threatened by the "Sunn pest," a bug that can destroy the value of wheat. Speed in confronting this pest is essential – even minor delays in use of pesticides can cut wheat yield by 90 percent, and if just ...
Philadelphia, Pa. (May 29, 2013) – Facial fractures are relatively common, and potentially serious, sports-related injuries among children participating in a wide range of sports, according to a study in the June issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS).
The five-year study provides insights into the characteristics of sports-related facial fractures in young athletes—including the causes and patterns of fractures in specific sports. "These data may allow targeted or sport-specific ...
