New findings show that ‘oligomers’ harm the integrity of cell membranes.
A report on the new discovery — by researchers from the United Kingdom, Spain, and Italy and published in the journal Science — describes what happens when the proteins come into contact with cells.
First study author Dr. Giuliana Fusco — of both Imperial College London and the University of Cambridge, both in the U.K. — says that the scientists hope that the findings will lead to improved drugs for Parkinson’s disease that stop the toxic proteins from getting into healthy brain cells.
Parkinson’s is a disease that gradually destroys the brain cells that produce a messenger chemical called dopamine, which is important for controlling movement.
The symptoms — which develop slowly and get worse over time — include impaired balance, rigidity, slowness of movement, tremors, and problems with speaking and swallowing.
Researchers have also discovered that Parkinson’s affects non-dopamine brain cells, which may explain why the disease often has symptoms that are not to do with movement, such as anxiety, depression, fatigue, and sleep disruption.
Although it most often strikes after the age of 50, around 10 percent of cases of Parkinson’s disease are diagnosed in people of a younger age.
Oligomers ‘disrupt cell membrane integrity’
In the new study, the researchers observed what happens when a protein called alpha synuclein malfunctions and forms into clusters called oligomers, which are toxic to brain cells.
They used solid-state nuclear magnetic resonance spectroscopy to characterize different structural features of the oligomers and then examined how the features influenced their interaction with the cells. They used brain cells from rats as well as brain cells sampled from human brain tumors.
The study is significant because the team found a way to keep the normally unstable oligomers stable for long enough to observe a level of detail that has not been seen before. Once they form, oligomers very quickly either enter cells, dissolve, or turn into long fibers.
By keeping the oligomers stable, the researchers were able to identify two features that are key to their toxicity: one that allows them to stick to the cell wall, and another that lets them penetrate the membrane and disrupt cell function.
“It is a bit like if you put a piece of extremely hot metal on to a plastic surface,” explains co-senior study author Dr. Alfonso De Simone, of the Department of Life Sciences at Imperial College London. “In a fairly short space of time it will burn a hole through the plastic.”
He suggests that the oligomer’s ability to “disrupt the integrity of the membrane” is a crucial step in the process that eventually kills the brain cell.
Both similar and different to viruses
In further experiments, the team found a way that might reduce oligomer toxicity. They found that altering its protein sequence made the oligomer less able to stick to the cell membrane.
The researchers likened the behavior of the oligomers and their propensity to stick to the walls of brain cells as similar to the way that viruses enter cells. The difference is that while a virus then adapts the cell machinery to its own end, the oligomer just disrupts it.
Dr. De Simone also suggests that oligomers are able to attach themselves to cell membranes because of “an accident of nature” that gives them the same features as normal membrane proteins that help with brain signaling.
“Just having this information doesn’t mean that we can now go and make a drug, but obviously if we can understand why these clumps of proteins behave the way they do, we can make faster scientific progress towards treating Parkinson’s disease.”
Dr. Giuliana Fusco