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.

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The researchers suggest a general breakdown of mitochondria is not the complete picture of what goes on inside brain cells in Parkinson’s disease.

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.

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.

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 stress rather 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:

Learn about another recent investigation into the link between faulty mitochondria and Parkinson’s disease.