Contact: Karen Kreeger
University of Pennsylvania School of Medicine
Penn study finds link between Parkinson's disease genes and manganese poisoning
PHILADELPHIA – A connection between genetic
and environmental causes of Parkinson's disease has been discovered by
a research team led by Aaron D. Gitler, PhD, Assistant Professor in the
Department of Cell and Developmental Biology at the University of
Pennsylvania School of Medicine. Gitler and colleagues found a genetic
interaction between two Parkinson's disease genes (alpha-synuclein and
PARK9) and determined that the PARK9 protein can protect cells from
manganese poisoning, which is an environmental risk factor for a
Parkinson's disease-like syndrome. The findings appear online this week
Manganism, or manganese poisoning,
is prevalent in such occupations as mining, welding, and steel
manufacturing. It is caused by exposure to excessive levels of the
metal manganese, which attacks the central nervous system, producing
motor and dementia symptoms that resemble Parkinson's disease.
Parkinson's patients, the alpha-synuclein protein normally found in the
brain misfolds, forming clumps. Yeast cells, the model system in which
Gitler studies disease proteins, also form clumps and die when this
protein is expressed at high levels. These are the same yeast cells
that bakers and brewers use to make bread, beer, and wine.
a postdoctoral fellow at the Whitehead Institute in Cambridge,
Massachusetts, Gitler and colleagues started looking for genes that
could prevent the cell death caused by mis-folded alpha-synuclein in
yeast. Eventually they found a few genes to test in animal models and
some were able to protect neurons from the toxic effects of
alpha-synuclein. "One of the genes that we found was a previously
uncharacterized yeast gene called YOR291W. No one knew what it did back
in 2006," he recalls.
In the meantime, researchers in Europe
published studies about a family that had an early-onset form of a type
of Parkinson's disease caused by mutations in the PARK9 gene. "When I
read about this study, I wondered what the closest yeast gene was to
the human PARK9 gene and it turned out to be YOR291W," explains Gitler.
"It was one of the genes that could rescue alpha-synuclein toxicity
from our yeast screen. That was the big Eureka! and completely
unexpected. It suggested that Parkinson's disease genes could interact
with each other in previously unexpected ways."
Because of its
similarity to the human PARK9 gene, Gitler and colleagues renamed the
yeast gene to YPK9 (which stands for Yeast PARK9). Researchers at
Purdue University and The University of Alabama teamed up with Gitler
and his colleagues to show that the PARK9 gene could also protect
neurons from alpha-synuclein's toxic effects.
Next, the team
set out to find the function of YPK9. Study co-first author,
postdoctoral fellow Alessandra Chesi, PhD, discovered that YPK9 encodes
a metal transporter protein. "Its sequence looks like other proteins
that we know transport metals," says Chesi.
She deleted the
YPK9 gene from yeast and the cells were fine. Then she exposed
YPK9-deficient yeast cells to an excess of different metals -- zinc,
copper, manganese, iron, etc. -- to determine which metal it might
transport. Of all the metals Chesi tested, she found that in the
presence of manganese, the YPK9-deficient yeast did not grow as well.
They were hypersensitive to manganese.
"This was astonishing,
because it was known for years that welders and miners that inhale
manganese get a Parkinson's-like disease called manganese poisoning,"
says Chesi. "The specific neurons that are lost in the miners are from
the globus pallidus, a brain motor center. The European parkinsonism
patients with the PARK9 mutation also lose neurons in this region."
then found that the protein made by YPK9, the yeast gene equivalent of
PARK9, is localized to the vacuole membrane in the yeast cell. Vacuoles
are inner cell components that wall off toxic substances for later
disposal. "Our hypothesis is that the vacuole, a bag in the cell that
captures toxins, is sitting there and taking in manganese and
sequestering it for detoxification, keeping it away from other cell
organelles," explains Gitler. "But, having a mutation in the PARK9 gene
causes problems for this process in yeast and possibly in humans".
an interesting story that we've discovered in yeast and it will be
important to see if it holds up in people. What's new is the connection
between genetic and environmental causes of Parkinson's. How does PARK9
protect against alpha-synuclein toxicity and how does PARK9 help
prevent manganese poisoning? This is what we will be investigating
This work was funded in part by a National Institute of Health Director's New Innovator Award.
is an inventor on patents and patent applications that have been
licensed to FoldRx Pharmaceuticals, a company that investigates drugs
to treat protein-folding diseases.
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