Parkinson's trigger observed for the first time in a human brain

BarcelonaAn international team of scientists has visualized and quantified for the first time in human brain tissue the protein groups considered to be the triggers of Parkinson's disease, an advance that may help unravel the mechanisms by which this neurological disease spreads through the brain and may support the development of diagnostics and potential treatments in the future. This is an important milestone, as the factors responsible for Parkinson's disease beginning to develop in the brain had until now evaded direct detection. The results were published this Wednesday in the journal Nature Biomedical Engineering.

For over a hundred years, doctors have recognized Parkinson's disease by the presence of large protein deposits, called Lewy bodies. These abnormal accumulations appear inside the brain's neurons and are composed primarily of oligomers of alpha-synuclein, a protein that normally intervenes in neuron communication. When they misfold, the proteins become oligomers, and under these conditions they become toxic. Scientists already suspected that smaller, precociously formed clumps could cause damage to brain cells, and now researchers from the University of Cambridge, University College London, the Francis Crick Institute in the United Kingdom, and Montreal Polytechnic have managed to see, count, and compare these protein clumps.

The main challenge in observing these signals was the size of the proteins, which are only a few nanometers in length. From the development of a new ultra-sensitive fluorescence microscopy imaging technique, called ASA-PD (for its acronym in English ofadvanced sensing of aggregates for Parkinson's disease), the international team was able to examine brain tissue samples from deceased people with Parkinson's and compared them to healthy individuals of a similar age.

The observation indicated that these protein clusters were present in both healthy brains and brains that had developed the disease, but with one difference: the size of the oligomers. In brains affected by the degenerative disorder, they were larger, brighter, and more numerous, suggesting a direct relationship with the progression of the disorder, according to co-author of the research, Lucien Weiss, an engineer at the Polytechnique de Montreal.

The team also discovered a subclass of these oligomers that appeared only in Parkinson's patients and that could be the first visible markers of the disease, possibly years before symptoms appear. Thanks to this tool, scientists were able to observe and analyze millions of oligomers in human brain tissue samples, something that was previously impossible. "This method doesn't just give us a snapshot," says Weiss, who says it also offers a comprehensive atlas of protein changes in the brain.

"Lewy bodies are the hallmark of Parkinson's, but they essentially indicate where the disease developed, not where it currently is," adds co-leader of the research, Steven Lee, of the Yusuf Hamied Department of Chemistry at the University of Cambridge. However, observing the disease in its early stages can reveal "much more about how the disease develops in the brain and how we might treat it," he stresses.

"A needle in a haystack"

Parkinson's is the second most prevalent neurodegenerative disease in the world. It is a chronic disorder that affects the nervous system and progressively develops into various forms of disability and dependency. The number of people affected worldwide is expected to double by 2050, reaching 25 million. Although there are medications that can help control some of the disease's symptoms, such as tremors and muscle stiffness, there are no drugs that can stop it.

However, there are also no tools to efficiently diagnose Parkinson's. "That's why the discovery described in the article is of great value, not only for understanding how the disease begins, but also for opening up new possibilities for diagnosis and treatments that modify the course of the disease, which are currently unavailable," says Salvador Ventura, scientific director of the Parc Taulí Research and Innovation Institute (I3PT-CERCA).

The researchers emphasized that visualizing these protein clusters was "like finding a needle in a haystack," but they emphasized the significance of the discovery, because knowing where they are could be essential for identifying specific cell types in certain brain regions. "The only real way to understand what happens in human diseases is to study the human brain directly, but due to its enormous complexity this represents a huge challenge," confirmed researcher Sonia Gandhi, from the Francis Crick Institute, who concludes: "We hope that overcoming this technological barrier will allow us to understand why, where and how the shape is formed.

In this sense, scientists argue that in the future these technologies could be applied to other neurodegenerative diseases, such as Alzheimer's or Hunt's disease. Ventura points out that these findings are difficult to apply as an early diagnosis method in clinical practice, since they are slow and very expensive processes, but admits: "Without a doubt, ASA-PD has the characteristics and the potential to become a crucial technique."