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From University of Buffalo Reporter

Finding key to Parkinson's

Double whammy on dopamine transport system suspected

By LOIS BAKER
Contributing Editor

Parkinson's disease may be caused by an environmental-genetic double
whammy
on the neurons that produce dopamine, the neurotransmitter that controls
body movement, a new study has shown.

UB researchers, using cultures of rat neurons, have shown that the
presence
of mutated parkin genes, combined with the toxic effects of the chemical
rotenone, results in a cascade of highly toxic free radicals, the
destruction of microtubules that transport dopamine to the brain's
movement
center, and eventual death of the dopamine-producing neuron.

"This study shows how an environmental toxin and a gene linked to
Parkinson's disease affect the survival of dopamine neurons by dueling on
a
common molecular target?microtubules?that are critical for the survival
of
dopamine-producing neurons," said Jian Feng, assistant professor of
physiology and biophysics in the School of Medicine and Biomedical
Sciences
and senior author.

"Based on these findings, we have identified several ways to stabilize
microtubules against the onslaught of rotenone. These results ultimately
may lead to novel therapies for Parkinson's disease."

Results of the research were presented on Sunday at the American Society
for Cell Biology meeting in Washington, D.C.

Researchers who study Parkinson's disease know that persons with a
mutation
in the parkin gene are at risk for the disease, and that exposure to
agricultural chemicals, including rotenone, cause Parkinson's-like
symptoms
in animals. In addition, long-term epidemiological studies of Parkinson's

disease patients have shown a strong link between exposure to
pesticides/herbicides and increased risk of developing the disease, Feng
noted.

Earlier research by several groups has shown that rotenone destroys only
neurons that produce dopamine, while largely sparing neurons that produce

other neurotransmitters. Feng's laboratory set out to answer the
questions
"Why?" and "How?"

By studying the effects of rotenone on rat neurons, they discovered that
one of the targets of the pesticide was microtubules?intracellular
highways
for transporting various chemicals such as dopamine to the brain area
that
controls body movement.

Normally the enzyme parkin would protect the neuron from rotenone's
assault
on microtubules, Feng said.

"When microtubules are broken down by rotenone, the disassociated protein

building blocks, called tubulin, are left behind," he said. "These
tubulins
are probably misfolded proteins. Left unattended, they could interfere
with
the normal assembly of microtubules. Based on our previous work that
parkin
marks this 'old' tubulin for rapid degradation, we theorize that parkin
may
thus prevent this interference."

Mutated parkin loses this protective ability, however, allowing rotenone
to
do its damage unchecked.

Feng and colleagues showed that rotenone damages the microtubules, which
prevents dopamine from reaching the brain's movement center, causing a
back-up in the dopamine transport system. Meanwhile, the backed-up
dopamine
accumulates in the neuron's cytoplasm and breaks down, causing a release
of
toxic free radicals that destroy the neuron.

Additional researchers on the study were Yong Ren, Wenhua Liu and Houbo
Jiang, postdoctoral associates in the Department of Physiology and
Biophysics.

The study was funded by a grant from the National Institutes of Health.

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