Nature's issue: The concept of Parkinson's disease is challenged

Release date: 2016-06-28

Parkinson's disease affects about seven to ten million people in the world. Suffering from the disease means gradually losing mobility and some mental disorders and cognitive impairment. The general view is that Parkinson's disease is caused by mitochondrial dysfunction. However, a recent study in Drosophila showed that neurodegeneration in Parkinson's disease is due to endoplasmic reticulum stress in cells, rather than previously thought to be mitochondrial dysfunction. The study found that disease-related neuronal death was inhibited when certain chemicals were used to block endoplasmic reticulum stress. The relevant research results are published in "Cell Death & Disease".

Some genetic forms of early-onset Parkinson's disease are usually attributed to mitochondrial dysfunction. Without a reliable source of energy, neurons will degenerate and die. This may not be all that happens in cells that are affected by Parkinson's disease. Researchers at the MRC Toxicology Department at the University of Leicester, UK, used common fruit flies for in-depth investigations; the use of fruit flies is because they provide a good genetic model for humans.

Studies conducted in human subjects have limited role in elucidating the signaling pathways and cellular processes behind neurodegenerative processes. This is because moral and technical constraints limit the extent of genetic analysis in humans.

Drosophila is an effective animal model for understanding the molecular mechanisms of human disease. This is because about 75% of human pathogenic genes are present in similar forms in fruit flies. At the same time, they are easy to operate, breed quickly, and there are many tools that can be used to manipulate any gene in the fruit fly. In fruit flies, potential treatments can be mixed with food and tested easily.

Studies have found that most of the damage to neurons with damaged mitochondria comes from a related but different source - the endoplasmic reticulum (ER) near the maze. ER has important protein folding work, so they can do most of the work in the cell. Misfolded proteins are recognized by cells as dangerous. If too many of these harmful proteins are present, the cells stop protein production. Although this system is protective, it also hinders the production of key proteins, which ultimately leads to the death of neurons.

To find out if ER stress may play a role in Parkinson's disease, a team led by Dr. Miguel Martins analyzed flies that carry a mutant form of the pink1 or parkin gene. Mutated forms of pink1 and parkin are known to starve to death due to the lack of energy in neurons by preventing the treatment of defective mitochondria. These genes are also mutated in humans and cause a hereditary version of the disease. Fruit flies carrying a mutation, much like Parkinson's patients, move more slowly and have weaker muscles. Insects struggle to fly forward, and their brains lose the typical characteristics of dopaminergic neurons, Parkinson's disease.

Miguel's team found that mutant fruit flies experienced a lot of ER stress compared to normal fruit flies. Mutant fruit flies cannot make proteins as fast as non-mutant fruit flies. They also have a high level of protein folding molecule BiP, a clear signal of stress.

One function of the pink1 and parkin genes is to help degrade the mitochondrial fusion protein (mitofusin), which links the endoplasmic reticulum to the mitochondria. The mutant fruit fly is rich in this protein. Studies have found that mutant flies have more mitochondria attached to ER than normal fruit flies. For this reason, the researchers believe that ER stress is associated with extra mitochondrial connections, preventing the defective version of organelles from being removed.

There are more of these connected mutant flies, with fewer dopaminergic neurons, which can have adverse effects on the brain. By reducing the number of these connections, neuronal loss can be prevented. When the researchers experimentally reduced the number of mitochondrial fusion proteins in mutant flies, although the mitochondria themselves were still defective, the number of connections decreased and the number of neurons increased again. The muscles of the fruit fly are still healthy.

These results suggest that neurodegeneration seen in Parkinson's disease is the result of ER stress rather than mitochondrial dysfunction. Scientists can prevent neurodegeneration in mutant flies by reducing mitochondrial fusion proteins or by blocking the effects of ER stress with chemicals.

Dr. Miguel Martins said: "This study poses a challenge to the widely accepted view that 'Parkinson's disease is caused by mitochondrial failure.' By identifying and preventing ER stress in disease models, we are likely to prevent neurodegenerative diseases. Such laboratory experiments allow us to see how ER stress affects Parkinson's disease. These results have only been applied to fruit flies so far, and we believe that further research can be found to be the same in humans. Interventions may help treat some forms of Parkinson's disease."

Source: Bio-Exploration

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