Marking a significant first, scientists have, for the first time, directly visualised and quantified the protein clusters believed to trigger Parkinson’s disease, signalling a major advance in the study of the world’s fastest-growing neurological disease, reports News-Medical.net.
These tiny clusters, called alpha-synuclein oligomers, have long been considered the likely culprits for Parkinson’s to start developing in the brain, but until now, they have evaded direct detection in human brain tissue.
Researchers from the University of Cambridge, University College London, the Francis Crick Institute and Polytechnique Montréal have now developed an imaging technique allowing them to see, count and compare oligomers in human brain tissue, a development one of the team says is “like being able to see stars in broad daylight”.
Their results, reported in Nature Biomedical Engineering, could help unravel the mechanics of how Parkinson’s spreads through the brain, and support the development of diagnostics and potential treatments.
By 2050, the number of people with Parkinson’s worldwide is expected to double to 25m, and although there are drugs that can help alleviate some of the symptoms, like tremor and stiffness, there are no drugs that can slow or stop the disease itself.
For more than a century, doctors have recognised Parkinson’s by the presence of large protein deposits called Lewy bodies. But scientists have suspected that smaller, earlier-forming oligomers may cause the damage to brain cells. Until now, these oligomers were simply too small to see – just a few nanometers long.
“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.”
Now, Lee and his colleagues have developed a technique called ASA-PD (Advanced Sensing of Aggregates for Parkinson’s Disease), which uses ultra-sensitive fluorescence microscopy to detect and analyse millions of oligomers in post-mortem brain tissue. Since oligomers are so small, their signal is extremely weak. ASA-PD maximises the signal while decreasing the background, dramatically boosting sensitivity to the point where individual alpha-synuclein oligomers can be observed and studied.
“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,” said co-first author Dr Rebecca Andrews, who conducted the work when she was a postdoctoral researcher in Lee’s lab. “It opens new doors in Parkinson’s research.”
The team examined post-mortem brain tissue samples from people with Parkinson’s and compared them to healthy individuals of similar age. They found that oligomers exist in both healthy and Parkinson’s brains.
The main difference between disease and healthy brains was the size of the oligomers, which were larger, brighter and more numerous in disease samples, suggesting a direct link to the progression of Parkinson’s.
The team also discovered a sub-class of oligomers that appeared only in Parkinson’s patients, which could be the earliest visible markers of the disease – potentially years before symptoms appear.
“This method doesn’t just give us a snapshot,” said Professor Lucien Weiss from Polytechnique Montréal, who co-led the research. “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.”
"The only real way to understand what is happening in human disease is to study the human brain directly, but because of its sheer complexity, this is very challenging,” said Professor Sonia Gandhi from The Francis Crick Institute, who co-led the research.
“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.”
Study details
Large-scale visualisation of α-synuclein oligomers in Parkinson’s disease brain tissue
Published in Nature Biomedical Engineering on 1 October 2025
Rebecca Andrews, Bin Fu, Christina Toomey et al.
Abstract
Parkinson’s disease (PD) is a neurodegenerative condition characterised by the presence of intraneuronal aggregates containing fibrillar ɑ-synuclein known as Lewy bodies. These large end-stage species are formed by smaller soluble protein nanoscale assemblies, often termed oligomers, which are proposed as early drivers of pathogenesis. Until now, this hypothesis has remained controversial, at least in part because it has not been possible to directly visualize nanoscale assemblies in human brain tissue. Here we present Advanced Sensing of Aggregates – Parkinson’s Disease, an imaging method to generate large-scale α-synuclein aggregate maps in post-mortem human brain tissue. We combined autofluorescence suppression with single-molecule fluorescence microscopy, which together enable the detection of nanoscale α-synuclein aggregates. To demonstrate the use of this platform, we analysed ~1.2 million nanoscale aggregates from the anterior cingulate cortex in human post-mortem brain samples from patients with PD and healthy controls. Our data reveal a disease-specific shift in a subpopulation of nanoscale assemblies that represent an early feature of the proteinopathy that underlies PD. We anticipate that quantitative information about this distribution provided by Advanced Sensing of Aggregates – Parkinson’s Disease will enable mechanistic studies to reveal the pathological processes caused by α-synuclein aggregation.
See more from MedicalBrief archives:
Parkinson’s ‘game changer’ research findings open up new possibilities
Parkinson’s breakthrough: New disease-causing mechanism found
‘Deep brain’ genes tied to Parkinson’s, ADHD – large global study