New Insight into Treating Parkinson's Disease


Neurodegeneration in Parkinson’s disease occurs from a failing mitochondrion.

New research using fruit flies found that the stress on the endoplasmic reticulum (ER) in the cell results in the neurodegeneration that occurs in Parkinson’s disease.

It was previously believed that the neurodegeneration occurred from a failing mitochondrion, but researchers found that there is more to the disease process.

Normally, the ER folds proteins so they can do the majority of work within cells. However, when the proteins are misfolded, the cell identifies them as being dangerous. If there are too many of these harmful proteins, then the cells will stop the protein production.

Although this process can be helpful, it also stalls the manufacture of vital proteins, resulting in neuron death. Researchers sought to determine if this ER stress played a role in Parkinson’s disease.

In the study, fruit flies with mutant forms of pink1 or parkin genes were analyzed since the mutations were already known to starve neurons of energy by stopping the disposal of defective mitochondria. The genes are also known to be mutated in humans and results in hereditary versions of the disease.

The results of the study showed that mutants had significant amounts of ER stress compared to normal fruit flies. The mutant flies were not able to manufacture proteins as quickly as non-mutants and had elevated levels of the protein-folding molecule BiP, a sign of stress.

A function of pink1 and parkin genes is to help degrade mitofusin, a protein that tethers the ER to mitochondria. In mutant flies, they had more of their mitochondria attached to the ER compared with normal flies.

The findings suggest that ER stress is related to this extra tethering of mitochondria, preventing the removal of defective versions of the organelle.

In the mutant fruit flies, they have more of these tethers and less of the dopaminergic neurons, which can have an adverse effect on the brain. Researchers hypothesized that if the number of tethers were reduced, it might prevent the loss of neurons.

Researchers tested the theory by lowering the amount of mitofusin in the mutants. The results showed that the amount of tethers dropped and the amount of neurons increased again.

Furthermore, the flies’ muscles were also found to remain healthy, even though the mitochondria were still defective. In addition to reducing mitofusin, researchers also used chemicals that blocked the effects of ER stress to prevent neurodegeneration in the mutant flies.

These findings suggest that the neurodegeneration in Parkinson’s disease is a result of ER stress instead of the failing mitochondria.

“This research challenges the current held belief the Parkinson’s disease is a result of malfunctioning mitochondria,” said lead researcher Miguel Martins. “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.”

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