Parkinson’s Protein Captured in Human Brains for the First Time

A new method can help scientists “see” the proteins that may trigger Parkinson’s disease (PD) in human brain tissue for the very first time.

PD, the second most common neurodegenerative disorder, is projected to affect 25.5 million people globally by 2050.

While drugs and interventions such as deep brain stimulation can alleviate some of the symptoms of PD, a cure has not yet been discovered, largely due to the challenge of studying the disorder’s pathophysiology.

The brains of PD patients are characterized by the presence of large protein aggregates, known as Lewy bodies. These protein “clumps” disrupt healthy neuronal function, particularly in a region known as the substantia nigra that is important for movement coordination.

Scientists have long believed that much smaller precursor proteins – known as α-synuclein oligomers – drive the disease in its earliest stages.

There’s just one problem: they’re so small that researchers have been unable to visualize oligomers in human brain tissue directly. Existing techniques have lacked the sensitivity required, meaning existing data on their potential role in PD has largely come from animal models. 

Professor Steven Lee and colleagues at the University of Cambridge, University College London, the Francis Crick Institute and Polytechnique Montréal have developed a solution: Advanced Sensing of Aggregates for Parkinson’s Disease, or ASA-PD for short.

Opening new doors in Parkinson’s research

ASA-PD is a novel optical detection and analysis platform that can quantify protein aggregate density, distribution and size directly in post-mortem human brain tissue using ultra-sensitive fluorescence microscopy.

In Nature Biomedical Engineering, Lee and team illustrated their technique on 15 post-mortem brain tissue samples obtained from PD patients and 15 samples from healthy matched controls.

Approximately 1.2 million oligomers were captured across the samples, producing the largest dataset on the prevalence, distribution and spatial location of α-synuclein aggregates in PD brains to date.

“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, a former postdoctoral researcher in Lee’s lab. “It opens new doors in PD research.”
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Protein clusters believed to trigger Parkinson’s are visualized

Using ASA-PD the researchers could see that oligomers are expressed both in PD brains and healthy controls, but in PD brains, they are larger.

“Their presence in control and disease suggests that small α-synuclein aggregates oligomerize under physiological conditions, where their formation and clearance are kept in balance by the protein homeostasis system,” the authors said.

PD brains also showed expression of a particular type of oligomer that was not expressed in healthy controls.

“These results suggest that a small proportion of the physiological oligomers that are detected in healthy controls may undergo a transition to the pathological large oligomers detected in PD,” Lee and colleagues explained. “Once this transition has occurred, these pathological oligomers may then ultimately aggregate further and become the fibrillar structures that are found in Lewy bodies and Lewy neurites.”

These images are from four brain samples: the two on top are samples of PD brains, and the two on the bottom are healthy controls. Alpha-synuclein is stained in red. Credit: Andrews et al.

ASA-PD can be integrated with other sophisticated protein technologies, including single-cell and spatial RNA analysis methods. The researchers predict its broader application will help to further identify the pathophysiological mechanisms underpinning not only PD, but other neurodegenerative diseases hallmarked by protein aggregation. 

Reference: Andrews R, Fu B, Toomey C, et al. Large-scale visualisation of α-synuclein oligomers in Parkinson’s disease brain tissue. Nat Biomed Eng. 2025. doi: 10.1038/s41551-025-01496-4