Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue
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Rebecca Andrews Bin Fu Christina E Toomey Jonathan C Breiter Joanne Lachica Joseph S Beckwith Ru Tian Emma E Brock Lisa-Maria Needham Gregory J Chant Camille Loiseau Angèle Deconfin Kenza Baspin Rebeka Popovic James Evans Yen Goh Begüm Kurt Lenart Senicar Marisa Edmonds Tim Bartels Nora Bengoa-Vergniory Peter J Magill Zane Jaunmuktane Oliver J Freeman Benjamin JM Taylor John Hardy Tammaryn Lashley Mina Ryten Michele Vendruscolo Nicholas W Wood Lucien E Weiss Sonia Gandhi Steven F Lee
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Abstract
Parkinson's disease (PD) is a neurodegenerative condition characterized 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.
Journal details
Journal
Nature Biomedical Engineering
Volume
10
Issue number
6
Pages
1222-1234
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10.1038/s41551-025-01496-4
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Europe PubMed Central
41034512
Pubmed
41034512
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The publication was previously a preprint.
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