Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue

Rebecca Andrews^#^{1

2

3

4}, Bin Fu^#^{1

2}, Christina E Toomey^#^{2

5

6}, Jonathan C Breiter^{1

2

7}, Joanne Lachica^{2

5

6}, Joseph S Beckwith^{1

2}, Ru Tian^{1

2

7}, Emma E Brock^{1

2}, Lisa-Maria Needham^{1

8}, Gregory J Chant^{1

2}, Camille Loiseau^{2

9}, Angèle Deconfin^{2

10}, Kenza Baspin¹⁰, Rebeka Popovic⁶, James Evans^{5

6}, Yen Goh⁶, Begüm Kurt¹¹, Lenart Senicar¹², Marisa Edmonds¹², Tim Bartels¹², Nora Bengoa-Vergniory^{11

13

14}, Peter J Magill^{2

9}, Zane Jaunmuktane^{2

5

15}, Oliver J Freeman^{16

17}, Benjamin J M Taylor³, John Hardy^{2

18}, Tammaryn Lashley^{2

18}, Mina Ryten^{2

19

20

21}, Michele Vendruscolo^{2

7}, Nicholas W Wood^{2

5}, Lucien E Weiss^{22

23}, Sonia Gandhi^{24

25

26}, Steven F Lee^{27

28}

Affiliations

¹ Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
² Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
³ Oncology R&D, AstraZeneca, Cambridge, UK.
⁴ Department of Chemistry, University of Zurich, Zurich, Switzerland.
⁵ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
⁶ The Francis Crick Institute, London, UK.
⁷ Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
⁸ Cambridge Advanced Imaging Centre, University of Cambridge, Cambridge, UK.
⁹ Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹⁰ Department of Engineering Physics, Polytechnique Montréal, Montréal, Québec, Canada.
¹¹ Achucarro Basque Center for Neuroscience, Leioa, Spain.
¹² UK Dementia Research Institute, University College London, London, UK.
¹³ Ikerbasque-Basque Foundation for Science, Bilbao, Spain.
¹⁴ Department of Neuroscience, University of the Basque Country, Leioa, Spain.
¹⁵ Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK.
¹⁶ Neuroscience BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
¹⁷ MSD R&D Innovation Centre, London, UK.
¹⁸ Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK.
¹⁹ UK Dementia Research Institute, University of Cambridge, Cambridge, UK.
²⁰ Great Ormond Street Institute of Child Health, University College London, London, UK.
²¹ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
²² Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA. lucien.weiss@polymtl.ca.
²³ Department of Engineering Physics, Polytechnique Montréal, Montréal, Québec, Canada. lucien.weiss@polymtl.ca.
²⁴ Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA. sonia.gandhi@crick.ac.uk.
²⁵ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. sonia.gandhi@crick.ac.uk.
²⁶ The Francis Crick Institute, London, UK. sonia.gandhi@crick.ac.uk.
²⁷ Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK. sl591@cam.ac.uk.
²⁸ Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA. sl591@cam.ac.uk.

^# Contributed equally.

PMID: 41034512
DOI: 10.1038/s41551-025-01496-4

Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue

Rebecca Andrews et al. Nat Biomed Eng. 2025.

. 2025 Oct 1.

doi: 10.1038/s41551-025-01496-4. Online ahead of print.

Authors

Affiliations

¹ Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
² Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
³ Oncology R&D, AstraZeneca, Cambridge, UK.
⁴ Department of Chemistry, University of Zurich, Zurich, Switzerland.
⁵ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
⁶ The Francis Crick Institute, London, UK.
⁷ Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
⁸ Cambridge Advanced Imaging Centre, University of Cambridge, Cambridge, UK.
⁹ Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹⁰ Department of Engineering Physics, Polytechnique Montréal, Montréal, Québec, Canada.
¹¹ Achucarro Basque Center for Neuroscience, Leioa, Spain.
¹² UK Dementia Research Institute, University College London, London, UK.
¹³ Ikerbasque-Basque Foundation for Science, Bilbao, Spain.
¹⁴ Department of Neuroscience, University of the Basque Country, Leioa, Spain.
¹⁵ Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK.
¹⁶ Neuroscience BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
¹⁷ MSD R&D Innovation Centre, London, UK.
¹⁸ Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK.
¹⁹ UK Dementia Research Institute, University of Cambridge, Cambridge, UK.
²⁰ Great Ormond Street Institute of Child Health, University College London, London, UK.
²¹ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
²² Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA. lucien.weiss@polymtl.ca.
²³ Department of Engineering Physics, Polytechnique Montréal, Montréal, Québec, Canada. lucien.weiss@polymtl.ca.
²⁴ Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA. sonia.gandhi@crick.ac.uk.
²⁵ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. sonia.gandhi@crick.ac.uk.
²⁶ The Francis Crick Institute, London, UK. sonia.gandhi@crick.ac.uk.
²⁷ Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK. sl591@cam.ac.uk.
²⁸ Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA. sl591@cam.ac.uk.

^# Contributed equally.

PMID: 41034512
DOI: 10.1038/s41551-025-01496-4

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.

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Conflict of interest statement

Declarations: Ethical approval for the study was granted by the Local Research Ethics committee of the National Hospital for Neurology and Neurosurgery. Competing interests: R.A., O.J.F. and B.J.M.T. were/are employed by AstraZeneca. O.J.F. is currently employed by MSD. All other authors declare no conflicts of interest.

References

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Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue

Affiliations

Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources