July 22, 2016University of Leicester
The
neurodegeneration that occurs in Parkinson’s disease is a result of stress on
the endoplasmic reticulum in the cell rather than failure of the mitochondria
as previously thought, according to a study in fruit flies. It was found that
the death of neurons associated with the disease was prevented when chemicals
that block the effects of endoplasmic reticulum stress were used.
Some inherited
forms of early-onset Parkinson’s disease have typically been blamed on poorly
functioning mitochondria, the powerhouses of cells. Without reliable
sources of energy, neurons wither and die. This may not be the complete picture
of what is happening within cells affected by Parkinson’s. Researchers from the
MRC Toxicology Unit at the University of Leicester used a common fruit fly to
investigate this further; fruit flies were used because they provide a good
genetic model for humans.
Studies
on human subjects are of limited use for elucidating the signaling pathways and
cellular processes underlying the neurodegenerative process. This is because
both ethical and technical constraints limit the extent to which genetic
analysis can be performed in humans.
Flies
are a well-established model animal to understand the molecular mechanisms of
human diseases. This is because about 75% of human disease-causing genes are
found in the fly in a similar form. Also, they are easy to work with, breed quickly
and many tools are available to manipulate any genes in the fly. In flies,
potential therapeutic drugs can be mixed with food and readily tested.
It
was found that the bulk of the damage to neurons with damaged mitochondria
stems from a related but different source -
the neighbouring maze-like endoplasmic reticulum (ER).
The
ER has the important job of folding proteins so that they can do the vast
majority of work within cells. Misfolded proteins are recognized by the cell as
being dangerous. Cells halt protein production if there are too many of these
harmful proteins present. While this system is protective, it also stalls the
manufacture of vital proteins, and this eventually results in the
death of neurons.
To
find out if ER stress might be at play in Parkinson’s, a team led by Dr Miguel
Martins analyzed fruit flies with mutant forms of the pink1
or parkin genes. Mutant forms of pink1 and parkin are
already known to starve neurons from energy by preventing the disposal
of defective mitochondria. These genes are also mutated in humans and result in
hereditary versions of the disease. Much like Parkinson’s patients, flies with
either mutation move more slowly and have weakened muscles. The insects
struggle to fly and they lose dopaminergic neurons in their brains –
a classic feature of Parkinson’s.
Compared
to normal flies, Miguel’s team found that the mutants experienced large amounts
of ER stress. The mutant flies did not manufacture proteins as quickly as the
non-mutants. They also had elevated levels of the protein-folding
molecule BiP, a telltale sign of stress.
One
function of pink1 and parkin genes is to help
degrade mitofusin - a protein that tethers the endoplasmic reticulum
to mitochondria. Mutant flies have an abundance of this protein. It was found
that the mutants had more of their mitochondria attached to the ER than normal
flies. For this reason, the researchers suggest that ER stress is related to
extra tethering of mitochondria, thereby preventing the removal of defective
versions of the organelle.
Mutant
flies, which have more of these tethers, have fewer dopaminergic neurons, which
can have an adverse effect on the brain. By reducing the number of these
tethers it is possible to prevent the loss of the neurons. When the researchers
experimentally lowered the amount of mitofusin in the mutants, the
number of tethers fell and the neuron number increased again (see figure). The
flies’ muscles also remained healthy despite the mitochondria themselves still
being defective.
These
results suggest that the neurodegeneration seen in Parkinson’s is a result of
ER stress rather than a general failure of the mitochondria. The scientists
were able to prevent neurodegeneration in mutant flies not only by
reducing mitofusin, but also with chemicals that block the effects of ER
stress.
Dr
Miguel Martins said: “This research challenges the current held belief the
Parkinson’s disease is a result of malfunctioning 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. While the finding so far only
applies to fruit flies, we believe further research could find that a similar
intervention in people might help treat certain forms of Parkinson’s.”
The
research has been published in the journal Cell Death and Disease and
a video explaining the main findings can be found
here
https://www.youtube.com/watch?v=13oA5eiH-8s (video will be
made public after embargo lifts)
http://www.labbulletin.com/articles/New-Findings-Challenge-Current-View-Origins-Parkinson-Disease#.V5PKv1e1WoM
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