For the first time, researchers have directly observed and measured a cluster of proteins thought to be responsible for Parkinson’s disease. This was a major milestone in understanding the world’s most rapidly progressing neurological disease.
These microscopic clusters, known as alpha-synuclein oligomers, have long been suspected of being the source of Parkinson’s disease, but until now they have not been detectable in human brain tissue.
A team from the University of Cambridge, UCL, the Francis Crick Institute and Polytechnique de Montréal has developed a powerful imaging approach that allows scientists to visualize, count and compare clusters of these proteins in human brain tissue. One researcher described this progress as “like being able to see stars in broad daylight.”
Published in natural biomedical engineeringThe discovery could transform the way scientists study Parkinson’s disease, provide new insights into how the disease spreads in the brain, and pave the way for earlier diagnosis and more targeted treatments.
Parkinson’s disease: a growing global health challenge
More than 166,000 people in the UK currently have Parkinson’s disease, and the number is expected to reach 25 million worldwide by 2050. Existing drugs can relieve symptoms such as tremors and stiffness, but they cannot stop or slow the progression of the disease.
For more than a century, doctors have identified Parkinson’s disease by the presence of large protein deposits known as Lewy bodies. But researchers have long believed that smaller, early-stage oligomers can actually cause damage to brain cells. Until now, it has been impossible to directly observe these microscopic structures, which are only a few nanometers long.
Diagnosing Parkinson’s disease from the early stages
“Lewy bodies are a hallmark of Parkinson’s disease, but essentially they tell us where the disease has been, rather than where we are now,” said Professor Stephen Lee from the Yusuf Hameed Department of Chemistry at the University of Cambridge, who co-led the study. “If we can observe Parkinson’s disease in its early stages, we will learn more about how the disease progresses in the brain and how it can be treated.”
To accomplish this, researchers developed a method called ASA-PD (Advanced Sensing of Parkinson’s Disease Aggregates). This ultra-sensitive fluorescence microscopy technique can detect and analyze millions of oligomers in postmortem brain samples. Oligomers are so small that the signal is weak, but ASA-PD enhances that signal while reducing background noise, allowing scientists to clearly see individual α-synuclein clusters for the first time.
shine a light on the invisible
“This is the first time we’ve been able to directly see oligomers in human brain tissue at this scale. It’s like seeing stars in broad daylight,” said co-first author Dr. Rebecca Andrews. She conducted this research while a postdoctoral researcher in Dr. Lee’s lab. “It opens new doors in Parkinson’s disease research.”
Researchers examined brain tissue from people with Parkinson’s disease and compared it with samples from healthy people of the same age. They found that oligomers were present in both groups, but the clusters were larger, brighter, and far more numerous in the Parkinson’s disease group. This difference suggests a strong relationship between oligomer growth and disease progression.
Clues to early signs of disease
The research team also identified a unique subset of oligomers found only in Parkinson’s disease patients. This may represent the earliest detectable sign of the disease and can appear years before symptoms appear.
“This method does more than just provide a snapshot,” said Lucien Weiss, a professor at the Polytechnic University of Montreal who co-led the study. “This provides a complete atlas of protein changes throughout the brain, and similar techniques could be applied to other neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease.
“Oligomers were the needle in the haystack, but now that we know where that needle is, it could help us target specific cell types in specific regions of the brain.”
A new window into the human brain
“The only real way to understand what’s going on in human disease is to study the human brain directly, but this is extremely difficult because the brain is so complex,” said Professor Sonia Gandhi of the Francis Crick Institute, who co-led the study. “We hope that by breaking through this technical barrier, we will be able to understand why, where and how protein clusters form, and how they alter the brain environment and cause disease.”
This research was made possible with support from Aligning Science Across Parkinson’s (ASAP), the Michael J. Fox Foundation and the Medical Research Council (MRC), which is part of UK Research and Innovation (UKRI). The research team expressed their gratitude to the patients, families, and caregivers who provided brain tissue for research and whose discoveries like these advance the understanding and potential treatment of Parkinson’s disease.
