Rice University study finds possible clues to epilepsy, autismDecember 09, 2008Rice University researchers have found a potential clue to the roots of epilepsy, autism, schizophrenia and other neurological disorders. While studying the peripheral nerves of the Drosophila, aka the fruit fly, Rice doctoral student Eric Howlett discovered an unanticipated connection between glutamate - an amino acid and neurotransmitter in much of the food we eat - and phosphoinositide 3-kinase (PI3K), an enzyme that, Howlett found, regulates the activity of neurons. Howlett and his colleagues, graduate student Curtis Chun-Jen Lin, research technician William Lavery and Michael Stern, a professor of biochemistry and cell biology, discovered that negative feedback mediated by PI3K regulates the excitability of neurons, an issue in a number of ailments that include neurofibromatosis, and that a mutation in a glutamate receptor gene common to both the fruit fly and humans has the ability to disrupt that regulatory mechanism. Howlett found the Drosophila's metabotropic glutamate receptor (DmGluRA) gene, when mutated, increased the excitability of the neuron by preventing PI3K from doing its job. Published online by the Public Library of Science Genetics, the study is the culmination of four years of work that built upon research by Marie-Laure Parmentier and her team at the University of Montpelier, France, to connect glutamate to regulatory functions in the fruit fly. "As science often goes, we didn't set out with this hypothesis," said Howlett, who began the project on funding obtained by Stern from the Department of Defense to study neurofibromatosis. "This all came about as a control for a completely different experiment, and we said, 'Wow, this is some interesting stuff.'" What he saw was that the overexpression of PI3K in motor neurons had a dramatic effect. "I noticed under the scope that these nerves were really big, and electrophysiologically, they were really slow. That wasn't what I expected, and it set me on a path of trying to find out what was going on." Howlett's breakthrough was identifying the negative feedback loop that acts to maintain neuronal excitability at normal levels. "What we found was that glutamate, which is released due to neuronal activity, feeds back onto metabotropic glutamate receptors on the same neurons that released it in the first place. This leads to the activation of PI3K and ultimately to the dampening of the amount of glutamate that is released." Without that regulation, he said, things inside the cell can go terribly wrong. "He put his heart and soul into this," said Stern of Howlett's exploration of the neuronal chain. "He was working on PI3K because that has a key role in neurofibromatosis. The Department of Defense is very interested in how PI3K is regulated in the nervous system because of its role in tumor formation." Discovering the negative feedback loop that keeps neurons stable was key, said Stern, but not the end of the investigation. "We know that glutamate activates mGluR and PI3K, but we don't know how," he said. "There are almost certainly a number of intermediates that remain to be identified, and we have several candidates we're looking into. "We're finding a mechanistic link among these molecules that hadn't been previously appreciated," Stern said. "Obviously the next step would be to test whether these same molecules are playing similar roles in mammalian neurons," said Howlett, who will leave Rice in the spring to pursue postdoctoral cancer research at Virginia Commonwealth University. A native Houstonian, he earned his bachelor's in biology at the University of Houston-Clear Lake. Howlett said mGluRs had already been targeted in possible treatments for schizophrenia, epilepsy and other "excitability" diseases, so it's not a stretch to think his research could lead to even more strategies in treating neurological ailments. "Actually, all of the molecules involved in our model have been implicated in one way or another with neurological diseases, but no one has been able to link them together into a coherent explanation of the diseases," he said. "Our model provides a novel framework that could really go a long way toward doing that." The paper can be found at: www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000277. Rice University |
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| Related Neurofibromatosis Current Events and Neurofibromatosis News Articles Loss of tumor supressor gene essential to transforming benign nerve tumors into cancers Researchers at UCLA's Jonsson Comprehensive Cancer Center showed for the first time that the loss or decreased expression of the tumor suppressor gene PTEN plays a central role in the malignant transformation of benign nerve tumors called neurofibromas into a malignant and extremely deadly form of sarcoma. New research strategy for understanding drug resistance in leukemia UCSF researchers have developed a new approach to identify specific genes that influence how cancer cells respond to drugs and how they become resistant. This strategy, which involves producing diverse genetic mutations that result in leukemia and associating specific mutations with treatment outcomes, will enable researchers to better understand how drug resistance occurs in leukemia and other cancers, and has important long-term implications for the development of more effective therapies. Anti-angiogenesis treatment improves hearing in some NF2 patients Treatment with the angiogenesis inhibitor bevacizumab improved hearing and alleviated other symptoms in patients with neurofibromatosis type 2 (NF2). Chromosomal problems affect nearly all human embryos For the first time, scientists have shown that chromosomal abnormalities are present in more than 90% of IVF embryos, even those produced by young, fertile couples. Mapping a clan of mobile selfish genes Much of human DNA is the genetic equivalent of e-mail spam: short repeated sequences that have no obvious function other than making more of themselves. Pediatric study finds alternatives for radiation of low-grade brain tumors A multi-institutional study led by researchers at The University of Texas M. D. Anderson Cancer Center has found that using chemotherapy alone and delaying or avoiding cranial radiation altogether can be effective in treating pediatric patients with unresectable or progressive low-grade glioma. Anti-cancer drug prevents, reverses cardiovascular damage in mouse model of premature aging disorder An experimental anti-cancer drug can prevent -- and even reverse -- potentially fatal cardiovascular damage in a mouse model of progeria, a rare genetic disorder that causes the most dramatic form of human premature aging, National Institutes of Health (NIH) researchers reported today. Gene's newly explained effect on height may change tumor disorder treatment A mutation that causes a childhood tumor syndrome also impairs growth hormone secretion, researchers at Washington University School of Medicine in St. Louis have found. Protein key to neuro-regeneration Researchers at the Peninsula Medical School in the South West of England, University College London, the San Raffaele Scientific Institute in Milan and Cancer Research UK, have for the first time identified a protein that is key to the regeneration of damage in the peripheral nervous system and which could with further research lead to understanding diseases of our peripheral nervous systems and provide clues to methods of repairing damage in the central nervous system. Research to lead to brain tumor therapies Unique human in vitro model (cell culture) research currently underway at the Peninsula Medical School in the South West of England is set to identify and develop therapies for the treatment of multiple tumours in the brain. More Neurofibromatosis Current Events and Neurofibromatosis News Articles |
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