06.22.06(Forbes) - Focusing on a protein that mysteriously
accumulates in the brains of people with Parkinson's disease,
researchers have discovered a biological pathway that might some day
lead to better treatments for the neurological condition.
Clumps of the protein, called alpha-synuclein, "are hallmarks of
Parkinson's disease," said Aaron Gitler, a postdoctoral researcher
in the laboratory of Susan Lindquist at the Whitehead Institute in
Cambridge, Mass. So, Gitlin and a fellow postdoctoral researcher,
Anil Cashikar, set out to determine whether preventing formation of
those clumps might prevent the death of neurons, the brain cells
whose deterioration causes the symptoms of Parkinson's.

They started with the simplest of organisms -- yeast cells -- using
an array engineered by the Harvard Institute of Proteonomics. The
researchers infected those cells with alpha-synuclein. They reasoned
that if they identified genes whose over-expression rescued a cell,
that would tell them something about how alpha-synuclein sickened a
cell in the first place.

Most of the genes they identified were involved in the production
and folding of cellular proteins into the proper shape and the fine-
tuning of those proteins. Then, working with researchers at the
University of Missouri, Kansas City, they showed that a mutated form
of alpha-synuclein destroyed a key protein in this process, causing
the cells to die.

The next step was to find a gene that increased production of this
key transport protein, to see if that would save the cells.

"We were surprised that when we tested this gene in higher animals --
fruit flies, worms, rat cells -- remarkably we could reverse
Parkinson's symptoms in higher animals," Gitler said. "There are
obvious implications for drug targets and the basic mechanism of how
the disease occurs."

The scientists tried several ways of increasing production of the
transport protein. In every case, the nerve cells were restored to
health, Gitler said.

The study findings appear in the June 23 issue of the journal
Science.

"The long-term goal is to find a drug target," said Cole M. Haynes,
who took part in the research at the University of Missouri and now
is a postdoctoral fellow at New York University School of
Medicine. "These proteins are the possible target," he said.

The progress made thus far is just a beginning, Gitler added. "We
hope that in the long run we can get a very good understanding of
this and other cellular defects," he said. "Knowing these details
will allow us and others to design therapies for Parkinson's disease
and other disease."

In a statement, Lindquist said, "We hoped that we could use these
simple model organisms to study something as deeply complex as
neurodegenerative disease. Most people thought we were crazy. But we
now not only have made progress in understanding this dreadful
disease, but we have a new platform for screening pharmaceuticals."

Dr. Michael S. Okun, medical director of the National Parkinson
Foundation and co-director of the University of Florida's Movement
Disorders Center, said the new study provides "potentially important
information for researchers interested in the neurodegenerative
process that leads to Parkinson's disease.

"The information from this study will be potentially useful to
investigators around the world interested in why brain cells die in
Parkinson's disease, and the results will hopefully be applied to
more complex research model systems," Okun said.

Parkinson's disease is a brain disorder that occurs when certain
nerve cells in the brain die or become impaired. Symptoms can
include tremors, slowness of movement, stiffness, trouble with
balance, muffled speech and depression.

An estimated 1.5 million Americans have the disease, with 60,000 new
cases diagnosed annually. The condition typically develops after age
65, according to the National Parkinson Foundation.


Clumps of the protein, called alpha-synuclein, "are hallmarks of
Parkinson's disease," said Aaron Gitler, a postdoctoral researcher
in the laboratory of Susan Lindquist at the Whitehead Institute in
Cambridge, Mass. So, Gitlin and a fellow postdoctoral researcher,
Anil Cashikar, set out to determine whether preventing formation of
those clumps might prevent the death of neurons, the brain cells
whose deterioration causes the symptoms of Parkinson's.

They started with the simplest of organisms -- yeast cells -- using
an array engineered by the Harvard Institute of Proteonomics. The
researchers infected those cells with alpha-synuclein. They reasoned
that if they identified genes whose over-expression rescued a cell,
that would tell them something about how alpha-synuclein sickened a
cell in the first place.

Most of the genes they identified were involved in the production
and folding of cellular proteins into the proper shape and the fine-
tuning of those proteins. Then, working with researchers at the
University of Missouri, Kansas City, they showed that a mutated form
of alpha-synuclein destroyed a key protein in this process, causing
the cells to die.

The next step was to find a gene that increased production of this
key transport protein, to see if that would save the cells.

"We were surprised that when we tested this gene in higher animals --
fruit flies, worms, rat cells -- remarkably we could reverse
Parkinson's symptoms in higher animals," Gitler said. "There are
obvious implications for drug targets and the basic mechanism of how
the disease occurs."

The scientists tried several ways of increasing production of the
transport protein. In every case, the nerve cells were restored to
health, Gitler said.

The study findings appear in the June 23 issue of the journal
Science.

"The long-term goal is to find a drug target," said Cole M. Haynes,
who took part in the research at the University of Missouri and now
is a postdoctoral fellow at New York University School of
Medicine. "These proteins are the possible target," he said.

The progress made thus far is just a beginning, Gitler added. "We
hope that in the long run we can get a very good understanding of
this and other cellular defects," he said. "Knowing these details
will allow us and others to design therapies for Parkinson's disease
and other disease."

In a statement, Lindquist said, "We hoped that we could use these
simple model organisms to study something as deeply complex as
neurodegenerative disease. Most people thought we were crazy. But we
now not only have made progress in understanding this dreadful
disease, but we have a new platform for screening pharmaceuticals."

Dr. Michael S. Okun, medical director of the National Parkinson
Foundation and co-director of the University of Florida's Movement
Disorders Center, said the new study provides "potentially important
information for researchers interested in the neurodegenerative
process that leads to Parkinson's disease.

"The information from this study will be potentially useful to
investigators around the world interested in why brain cells die in
Parkinson's disease, and the results will hopefully be applied to
more complex research model systems," Okun said.

Parkinson's disease is a brain disorder that occurs when certain
nerve cells in the brain die or become impaired. Symptoms can
include tremors, slowness of movement, stiffness, trouble with
balance, muffled speech and depression.

An estimated 1.5 million Americans have the disease, with 60,000 new
cases diagnosed annually. The condition typically develops after age
65, according to the National Parkinson Foundation.