Their new technique, published today in Nature Biomedical Engineering, could support the development of diagnostics and treatments for Parkinson’s disease in the future.

Parkinson’s disease is the world’s fastest-growing neurological disease. Affecting around 166,000 people in the UK currently, the disease is expected to affect 25 million worldwide by 2050. While there are drugs that help alleviate some of the symptoms of Parkinson’s disease, such as tremor and stiffness, there are no drugs that can slow or stop the disease itself. 

Sonia Gandhi, Assistant Research Director at the Crick and Professor of Neurology at UCL, splits her time between the lab and treating people with Parkinson’s disease at the National Hospital for Neurology and Neurosurgery. Her research seeks to understand the molecular mechanisms that drive neurodegenerative diseases, particularly by building models of the brain in a dish from patient-derived stem cells.

Growing neurons in a dish that mimic the course of the disease has made huge progress in developing new treatments and prevention. But for Sonia and other scientists in the field, the goal is to detect what’s changing in the brains of people with Parkinson’s disease without having to cultivate cells in the lab. 

“The only real way to understand what’s happening in human disease is to study the human brain directly, but because of the brain’s sheer complexity, this is very challenging,” she says. 

Seeing stars in broad daylight

For more than a century, doctors have recognised Parkinson’s disease by the presence of large protein deposits in the brain called Lewy bodies. But scientists have suspected that smaller, earlier-forming protein chains, or 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,” says Steven Lee co-lead author on the study from Cambridge’s Yusuf Hamied Department of Chemistry. “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.”

Steven and Sonia joined forces with Lucien Weiss from the Polytechnique Montreal to tackle this problem: how to visualise these tiny clusters, called alpha-synuclein oligomers, directly in human tissue. 

The team’s technique, called ASA-PD (Advanced Sensing of Aggregates for Parkinson’s Disease), 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 week, but the ASA-PD technique maximises the signal while decreasing the background, dramatically boosting sensitivity to allow the individual oligomers to 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,” says co-first author 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 new protocol identified hundreds of detectable aggregates of alpha-synuclein, a protein that becomes dysregulated in Parkinson's disease, in brains from people with Parkinson's disease (top panels) and healthy controls (bottom panels). The team applied robust computational methods to detect differences between the two sample types.

Identifying disease triggers

The team examined post-mortem brain tissue samples from people with Parkinson’s disease and compared them to healthy individuals of the same age. They found that oligomers exist in both healthy brains and brains from people with Parkinson’s disease, but the main difference was the size of the oligomers, which were larger, brighter and more numerous in disease samples, suggesting a direct link to the progression of the disease. 

The researchers also observed a sub-class of oligomers that appeared only in people with Parkinson’s disease, which could be the earliest viable markers of the condition, appearing potentially years before symptoms appear. 

“This method doesn’t just give us a snapshot,” says Lucien. “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.” 

Sonia agrees that the new technique paves the way for a deeper understanding of what’s happening at the earliest stages of Parkinson’s disease, adding, “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.