Scientists from the University of Cambridge, UCL, the Francis Crick Institute, and Polytechnique Montréal have directly observed and measured protein clusters thought to trigger Parkinson’s disease in human brain tissue for the first time. These clusters, known as alpha-synuclein oligomers, have been suspected of playing a key role in the onset of Parkinson’s but had not previously been detected directly due to their small size.
The research team developed an imaging technique called ASA-PD (Advanced Sensing of Aggregates for Parkinson’s Disease), which uses highly sensitive fluorescence microscopy to detect and analyze millions of these oligomers in post-mortem brain samples. This method enhances the signal from the tiny protein clusters while reducing background noise, making it possible to observe individual oligomers.
“Lewy bodies are the hallmark of Parkinson’s, but they essentially tell you where the disease has been, not where it is right now,” said Professor Steven Lee from Cambridge’s Yusuf Hamied Department of Chemistry, who co-led the research. “If we can observe Parkinson’s at its earliest stages, that would tell us a whole lot more about how the disease develops in the brain and how we might be able to treat it.”
Dr. Rebecca Andrews, co-first author and former postdoctoral researcher in Lee’s lab, described the significance: “This is the first time we've been able to look at oligomers directly in human brain tissue at this scale: it’s like being able to see stars in broad daylight. It opens new doors in Parkinson’s research.”
By comparing samples from people with Parkinson’s disease and healthy individuals of similar age, researchers found that both groups had oligomers present. However, those with Parkinson's had larger, brighter, and more numerous oligomers. The team also identified a subclass of oligomers unique to patients with Parkinson's disease; these may serve as early markers before symptoms develop.
“This method doesn’t just give us a snapshot,” said Professor Lucien Weiss from Polytechnique Montréal, who co-led the study. “It offers a whole atlas of protein changes across the brain, and similar technologies could be applied to other neurodegenerative diseases like Alzheimer’s and Huntington’s.
“Oligomers have been the needle in the haystack, but now that we know where those needles are, it could help us target specific cell types in certain regions of the brain.”
Professor Sonia Gandhi from The Francis Crick Institute added: “The only real way to understand what is happening in human disease is to study the human brain directly, but because of the brain’s sheer complexity, this is very challenging. We hope that breaking through this technological barrier will allow us to understand why, where and how protein clusters form and how this changes the brain environment and leads to disease.”
The findings were published in Nature Biomedical Engineering. The research received support from Aligning Science Across Parkinson’s (ASAP), The Michael J. Fox Foundation for Parkinson's Research (MJFF), and UK Research and Innovation's Medical Research Council (MRC). The team acknowledged patients and families who donated tissue for scientific use.
By 2050 global cases of Parkinson's are expected to double from current estimates—about 166,000 people live with it in the UK alone—and there are currently no drugs available that slow or stop progression; existing treatments address only symptoms such as tremor or stiffness.