Scientists have, for the first time, directly visualised and counted tiny protein clusters in the human brain that may be the earliest triggers of Parkinson’s disease.
The clusters – called alpha-synuclein oligomers – have long been suspected as the culprits behind the world’s fastest-growing neurological disorder, but until now they have never been seen in brain tissue.
To detect the evasive proteins, researchers developed a new imaging technique, dubbed Advanced Sensing of Aggregates for Parkinson’s Disease (ASA-PD), that makes these nanometre-scale (that’s one billionth of a metre) oligomers visible.
For decades, doctors have only been able to formally detect Parkinson’s by spotting Lewy bodies – large clumps of protein that build up in nerve cells. But many scientists suspect the disease actually begins with much smaller, earlier-forming oligomers.
“You can think of Lewy bodies as the kind of tombstone of the disease,” Prof Steven Lee from Cambridge’s Yusuf Hamied Department of Chemistry, who co-led the research, told BBC Science Focus. “They tell you where the disease has been in the brain, not where it is.”
To track down the earlier phases of the disease, the team compared post-mortem brain samples from people with Parkinson’s to those from healthy individuals. Oligomers were present in both those with the disease and the healthy brains – a surprise to the scientists – but were larger, brighter and more numerous in the brains of those with Parkinson's.
“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.
The researchers also found subtle differences in the distribution of oligomers, which could mark the earliest stages of disease years before symptoms appear.
Lee stressed that while the study is an important step forward, it should not be mistaken for an immediate precursor to finding a treatment. “We’re not at that stage,” he said. “Really, what this does is allow us to get a handle on those very early stages of the disease. In terms of treatment, this work is planting the seeds so we can grow the trees to bear the fruits.”
Currently, Parkinson’s, which affects more than 10 million people worldwide, has no treatments which directly tackle the disease itself. While current drugs can ease symptoms, such as shaking, nothing can attack the root cause of the disease and halt its progression.
The team, spanning the University of Cambridge, University College London, the Francis Crick Institute and Polytechnique Montréal, hopes that mapping these oligomers could eventually lead to diagnostic tests and new ways to track whether experimental drugs are working.
The technique could also be applied beyond Parkinson’s. “This method doesn’t just give us a snapshot,” said Prof 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 findings were published in Nature Biomedical Engineering.
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