Researchers reverse Parkinson's
symptoms in animal models
CAMBRIDGE, Mass. (June 22, 2006) — Statistics
for neurological disorders are grim. More than a million
Americans suffer from Parkinson's disease alone—a
number that is expected to soar over the next few decades
as the population ages. No current therapies alter the
fundamental clinical course of the condition.
Now, scientists at Whitehead Institute, in collaboration
with colleagues at several research centers, including
the University of Missouri's School of Biological Sciences,
have identified a key biological pathway that, when obstructed,
causes Parkinson's symptoms. Even more importantly, they
have figured out how to repair that pathway and restore
normal neurological function in certain animal models.
"For the first time we've been able to repair dopaminergic
neurons, the specific cells that are damaged in Parkinson's
disease," says Whitehead Member and Howard Hughes
Medical Institute Investigator Susan
Lindquist, senior author on the paper that will be
published June 22 online in Science.
“This gives a whole new direction for
understanding what's been going wrong in these
patients, and for considering much better strategies
for treating people,” says Antony Cooper
from the University of Missouri, Kansas City. |
In 2003, researchers in the Lindquist lab described
using yeast cells as "living test tubes" in
which they could study Parkinson's. A paper published
in Science reported that when a Parkinson's-related
protein called alpha-synuclein was over-expressed in
these cells, clumps of misshapen proteins gathered near
the membrane, and in many cases the cells either became
sick or died.
Aaron Gitler and Anil Cashikar, postdoctoral researchers
in the Lindquist lab, decided to follow up on these
results by asking a simple question: Is it possible
to rescue these cells when an over-expression of alpha-synuclein
would normally make them sick?
They began with an array of yeast cells in which each
cell over-expressed one particular gene. This array,
prepared by scientists at the Harvard Institute of Proteomics,
covers the entire yeast genome. All cells were also
infected 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
made the cell sick in the first place.
Most of the proteins that they identified pointed to
a pathway that involves two cellular organelles, the
endoplasmic reticulum (ER) and the Golgi. The ER is
the cell's protein factory, where proteins assume their
requisite shapes. Once a protein has properly folded,
it is trafficked over to the Golgi, where it is fine-tuned
and further prepared for its designated task.
Working with Antony Cooper from the University of Missouri,
Kansas City, Lindquist's team demonstrated that when
alpha-synuclein becomes mutated and clumps at the cell
surface, it manages to drag away a protein that helps
transport between the ER and the Golgi. Proteins are
blocked from navigating this crucial route, and the
cell dies.
This isn't just a general toxic effect caused by any
misfolded protein. It is specific to alpha-synuclein,
the protein associated with Parkinson's Disease.
"All this was done in yeast," says Gitler.
"Our next goal was to find out what this told us
about actual neurons."
If mutations of alpha-synuclein dragged the ER/Golgi
transport protein away from doing its job, as the yeast
research indicated, then cell death might be averted
simply by increasing the levels of this transport protein.
Working with colleagues at University of Pennsylvania,
University of Alabama, and Purdue University, the consortium
tested this hypothesis in the fruit fly, C. elegans
worm, and in neurons culled from rats-all of which had
alpha-synuclein-induced Parkinson's symptoms. In every
case, symptoms were reversed by increasing levels of
this transport protein.
"We tried this a number of different ways, from
creating transgenic animals that naturally over-expressed
this protein, to injecting a copy of the gene for this
transport protein into the neurons through a gene-therapy
technique," says Gitler. "In all cases the
results were the same. Cell death ceased, and the neurons
were restored to normal health."
"Protein folding problems are universal, so we
hoped we could use these simple model organisms to study
something as deeply complex as neurodegenerative disease,"
says Lindquist, who is also a professor of biology at
MIT. "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."
These findings also help explain why biopsies from Parkinson's
patients indicate stress in the ER of dopaminergic neurons.
"This gives a whole new direction for understanding
what's been going wrong in these patients, and for considering
much better strategies for treating people," says
Cooper.
The work was supported by the National Institutes of
Health.
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