June 24, 2016
The researchers suggest a general breakdown of mitochondria is not the complete picture of what goes on inside brain cells in Parkinson's disease.
The death of brain cells in
Parkinson's disease is likely a result of stress in their endoplasmic reticulum
or protein-folding machinery rather than just a general failure of their
mitochondria or powerhouses.
So
conclude researchers from the University of Leicester in the United Kingdom,
who report their findings, based on research conducted in fruit flies, in the
journal Cell Death and Disease.
Dr.
Miguel Martins, who heads a group in the MRC Toxicology Unit at Leicester,
says:
"This
research challenges the current held belief the Parkinson's disease is a result
of malfunctioning mitochondria."
He and
his colleagues used fruit flies because they provide a good genetic model for
studying humans - the insects carry about 75 percent of the genes that cause
human disease. Due to obvious ethical and technical constraints, it is not
possible to experiment with signaling pathways and cellular processes
underlying brain-wasting diseases in humans.
The
chief hallmark of Parkinson's disease is the death of
dopamine-producing cells in a part of the brain that controls a number of
functions, including movement. As the devastating disease progresses, more and
more brain cells die and patients gradually lose their ability to walk, talk,
and take care of themselves.
Two
genes - pink1 and parkin - are known to be mutated in humans with hereditary
versions of Parkinson's disease. Fruit flies with either of these mutations
also show classic features of Parkinson's disease - they have weak muscles,
move slowly, struggle to fly, and show loss of dopamine cells in their brains.
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Blocking ER stress prevented brain cell death
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Previous
studies have suggested that some inherited forms of Parkinson's disease are the
result of faulty mitochondria - the powerhouses inside cells that provide the
energy they need to function. If their mitochondria stop working, brain cells
wither and die.
However,
in the new study, the researchers suggest a general breakdown of mitochondria
is not the complete picture of what goes on inside cells in Parkinson's
disease. Instead, they suggest stress on the endoplasmic reticulum
(ER) - and its knock-on effect on mitochondria - is the key event.
Using
fruit flies, they showed that chemicals that block the effects
of stress on the ER prevented the death of brain cells associated
with Parkinson's disease.
The ER
is a maze-like compartment inside cells that has the important job of folding
proteins into the correct shapes for carrying out the essential work of cells.
If the ER starts producing misfolded proteins, the cell shuts it down. While
this protects the cell up to a point, eventually it causes the cell to die.
The
team found that fruit flies with mutations in pink1
and parkin experienced large amounts of ER stress. They did not make
proteins as well or as fast as normal flies, and they had higher levels of a
protein-folding molecule called BiP - a known marker of ER stress.
ER stress linked to extra tethering of mitochondria
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The ER is tethered to mitochondria
via a protein called mitofusion. The breakdown of the protein is controlled by
pink1 and parkin. An important aspect of this is letting go of mitochondria
that have stopped working so they can be removed and disposed of.
However, the researchers found
that the flies with mutated versions of pink1 and parkin had more of their
mitochondria attached to the ER than normal flies. This led them to conclude
that the ER stress is linked to extra tethering of mitochondria, thus
blocking the release of faulty ones.
The team also found that flies
with mutated versions of pink1 and parkin, which have more of these tethers,
also have fewer dopamine-producing brain cells, the classic hallmark of
Parkinson's disease.
In a further experiment, the
researchers lowered the levels of mitofusion in the mutant flies and showed
this led to reduction in numbers of mitochondria tethered to the ER, and
prevented death of brain cells. Also, the flies' muscles remained strong, even
though they had defective mitochondria.
The researchers suggest these
findings show the death of brain cells seen in Parkinson's disease stems from
ER stressrather than a general failure of mitochondria.
"By identifying and
preventing ER stress in a model of the disease it was possible for us
to prevent neurodegeneration. Lab experiments, like this, allow us to see what
effect ER stress has on Parkinson's disease."
Dr. Miguel Martins
So far, the results only apply to
fruit flies, but the team believes further investigations will show that
something similar could work in humans to treat certain forms of Parkinson's
disease.
The following video summarizes the
findings and their implications:
http://www.medicalnewstoday.com/articles/311203.php
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