Scientists have, for the first time, directly visualised and quantified the protein clusters believed to trigger Parkinson's, marking a major advance in the study of the world's fastest-growing neurological disease.
These tiny clusters, called alpha-synuclein oligomers, have long been considered the likely culprits for Parkinson's disease to start developing in the brain, but until now, they have evaded direct detection in human brain tissue.
Now, researchers from the University of Cambridge, UCL, the Francis Crick Institute and Polytechnique Montréal have developed an imaging technique that allows 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 the journal 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.
Around 166,000 people in the UK live with Parkinson's disease, and the number is rising. By 2050, the number of people with Parkinson's worldwide is expected to double to 25 million. While there are drugs that can help alleviate some of the symptoms of Parkinson's, such as 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 nanometres 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 different 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, wo 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 the brain's 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."
The research was supported in part by Aligning Science Across Parkinson's (ASAP), the Michael J. Fox Foundation, and the Medical Research Council (MRC), part of UK Research and Innovation (UKRI). The researchers thank the patients, families and carers who donated tissue to brain banks to enable this work to happen.
