BUFFALO, N.Y. -- Neuroscientists from the University atBuffalo have described for the first time how rotenone, anenvironmental toxin linked specifically to Parkinson's disease,selectively destroys the neurons that produce dopamine, theneurotransmitter critical to body movement and muscle control.
Microtubules,intracellular highways that transport dopamine to the brain area thatcontrols body movement, are the crucial target, they report.
Damageto microtubules prevents dopamine from reaching the brain's movementcenter, causing a back-up of the neurotransmitter in the transportsystem, the researchers found. The backed-up dopamine accumulates inthe body of the neuron and breaks down, causing a release of toxic freeradicals, which destroy the neuron.
The study appeared in the Aug. 9 issue of the Journal of Biological Chemistry.
"Thisstudy shows how an environmental toxin affects the survival of dopamineneurons by targeting microtubules that are critical for the survival ofdopamine-producing neurons," said Jian Feng, Ph.D., assistant professorof physiology and biophysics in the UB School of Medicine andBiomedical Sciences and senior author on the study.
"Based onthese findings, we have identified several ways to stabilizemicrotubules against the onslaught of rotenone. These resultsultimately may lead to novel therapies for Parkinson's disease."
Atleast 500,000 people are believed to suffer from Parkinson's disease inthe United States, and about 50,000 new cases are reported annually,according to the National Institutes of Health. These figures areexpected to increase as the population ages: The average age of onsetis about 60. The disorder appears to be slightly more common in menthan women.
Feng and colleagues in the Department of Physiologyand Biophysics have concentrated their research on the cellularmechanisms of the disease. They are interested specifically inunderstanding why rotenone destroys neurons that produce dopamine,while sparing neurons that produce other neurotransmitters.
Usingcultures of rat neurons, the researches subjected neurons that producevarious types of neurotransmitters to agents that mimic the action ofrotenone. These results showed that dopaminergic neurons were destroyedwhile others survived.
They then topped off the treatment byadding the drug taxol, which stabilizes microtubules and prevents theirbreakdown. Findings showed that by protecting microtubules, the toxiceffect of rotenone on dopamine-producing neurons was greatly reduced.
"Basedon these findings, we believe that microtubules are a critical targetof PD environmental toxins such as rotenone," said Feng. "Since manymicrotubule-depolymerizing agents are compounds naturally produced inmany plants, our research points to the need to examine their possiblelink to Parkinson's disease. In addition, PD has a higher incidence inrural areas and is associated with pesticides and insecticidesfrequently used in farming practices."
The research also opens upnovel avenues for the development of PD therapies by targetingmicrotubules, he said. Feng and colleagues in his laboratory areworking actively towards this goal.
Additional researchers on thestudy were Yong Ren, Ph.D., Wenhau Liu, Ph.D., Houbo Jiang, Ph.D., andQian Jiang, Ph.D., post-doctoral associates in the Department ofPhysiology and Biophysics.
The research is funded by a grant from the National Institutes of Health.
TheUniversity at Buffalo is a premier research-intensive publicuniversity, the largest and most comprehensive campus in the StateUniversity of New York.
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