Stabilizing microtubules with L-AP4 reduces rotenone toxicity
Apr 19, 2006 - 8:01:00 PM, Reviewed by: Dr. Ankush Vidyarthi
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They showed that rotenone kills dopamine neurons by destroying microtubules, and that stabilizing microtubules greatly reduces the toxicity of rotenone.
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By University at Buffalo,
Researchers at the University at Buffalo affiliated with the New York State Center of Excellence in Bioinformatics and Life Sciences have identified a novel agent that can protect neurons involved in Parkinson's disease from being destroyed by the pesticide rotenone.
The agent, called L-AP4, activates a critical group of receptors called group III metabotropic glutamate receptors and may be a promising drug target. Currently there is no known cure for Parkinson's disease.
Long-term studies have shown that environmental toxins play a critical role in the development of Parkinson's disease, and it has been shown recently in research with rats that administering rotenone, a naturally occurring substance widely used as a pesticide, destroys dopamine-producing neurons and causes symptoms of Parkinson's disease in this animal model.
In the April 19 issue of The Journal of Neuroscience, UB researchers lead by Jian Feng, Ph.D., report that activation of group III metabotropic glutamate receptors reverses a cascade of events triggered by rotenone that destroys dopamine neurons.
Feng, UB associate professor of physiology and biophysics, and colleagues earlier demonstrated that microtubules, the intracellular highways for transporting dopamine and many vital cellular components, are critical for the survival of dopamine neurons, which are responsible for controlling body movement.
They showed that rotenone kills dopamine neurons by destroying microtubules, and that stabilizing microtubules greatly reduces the toxicity of rotenone.
In this new study, Feng's group has found that activation of group III metabotropic glutamate receptors by drugs such as L-AP4 triggers a chain of events that leads to microtubule stabilization. This cascade, called the MAP kinase pathway, activates several enzymes that regulate the stability of microtubules.
The primary symptoms of Parkinson's disease are tremors, slowness in movements, and impaired balance and coordination. At least 500,000 people are believed to suffer from Parkinson's disease in the United States, and about 50,000 new cases are reported annually, according to the National Institutes of Health. These figures are expected to increase as the population ages: The average age of onset is about 60. The disorder appears to be slightly more common in men than women. 
- April 19 issue of The Journal of Neuroscience
www.buffalo.edu
Additional authors on the paper are Qian Jiang, Ph.D., postdoctoral associate, and Zhen Yan, Ph.D., associate professor, both in the UB Department of Physiology and Biophysics. Feng and Yan are members of the Neurodegenerative Disease Team with UB's New York State Center of Excellence in Bioinformatics and Life Sciences.
The research is funded by a grant to Feng from the National Institutes of Health.
The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York.
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