Differential pathological dynamics triggered by distinct Parkinson patient–derived α-synuclein extracts in nonhuman primates
The presence of α-synuclein (α-syn) aggregates, such as Lewy bodies in patients with Parkinson's disease (PD), contributes to dopaminergic cell death. Injection of PD patient-derived α-syn in nonhuman primates has illustrated the exquisite vulnerability of primate dopaminergic neurons. Here, we aimed to elucidate the temporal and spatial pathological changes induced by two distinct α-syn pathogenic structures, having large or small sizes. To unravel the underlying molecular pathways, we conducted a proteomic analysis of the putamen and the entorhinal cortex, two brain regions carrying notable α-syn pathology. We demonstrate that distinct assemblies of α-syn aggregates drive unique pathogenic changes that ultimately result in a comparable extent of nigrostriatal degeneration at the level of nigral dopaminergic neuron cell bodies and striatal dopaminergic terminals. More broadly, our findings identify pathogenic trajectories associated with large or small α-syn aggregates, suggesting the existence of several possible concomitant pathogenic routes in PD.
Authors
- Benjamin Dehay (ORCID: https://orcid.org/0000-0003-1723-9045)
- Erwan Bézard (ORCID: https://orcid.org/0000-0002-0410-4638)
- Marie-Laure Arotçarena (ORCID: https://orcid.org/0000-0002-1306-3700)
- Morgane Darricau (ORCID: https://orcid.org/0000-0002-6663-3156)
- Caroline Tokarski (ORCID: https://orcid.org/0000-0001-7296-3330)
- Niels Kruse (ORCID: https://orcid.org/0000-0002-4036-8999)
- Grégory Porras (ORCID: https://orcid.org/0000-0003-4710-1637)
- Sylvain Bohic (ORCID: https://orcid.org/0000-0001-6355-7592)
- Rémi Kinet (ORCID: https://orcid.org/0000-0002-7737-6837)
- Sandrine Camus (ORCID: https://orcid.org/0000-0001-6427-7357)
- Nuria García‐Carrillo (ORCID: https://orcid.org/0000-0002-3437-9974)
- Évelyne Doudnikoff (ORCID: https://orcid.org/0000-0002-3770-8585)
- Inés Trigo‐Damas (ORCID: https://orcid.org/0000-0002-7821-2973)
- Stéphane Claverol (ORCID: https://orcid.org/0000-0001-5315-2823)
- Michele Morari (ORCID: https://orcid.org/0000-0002-4601-4454)
- Sandra Doveró (ORCID: https://orcid.org/0000-0002-5781-1328)
- Monika Goikoetxea (ORCID: https://orcid.org/0000-0001-6738-9733)
- Miquel Vila (ORCID: https://orcid.org/0000-0002-1352-989X)
- Jose Angel Obeso (ORCID: https://orcid.org/0000-0002-6996-8613)
- María Trinidad Herrero (ORCID: https://orcid.org/0000-0003-4953-1446)
- Mathieu Bourdenx (ORCID: https://orcid.org/0000-0002-9799-9222)
- Brit Mollenhauer (ORCID: https://orcid.org/0000-0001-8437-3645)
- Marie-Laure Thiolat (ORCID: https://orcid.org/0000-0003-2586-756X)
- Cristina Estrada (ORCID: https://orcid.org/0009-0004-0405-2008)
Institutions
- Universidad San Pablo CEU (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universitat Autònoma de Barcelona (ES)
- Centre National de la Recherche Scientifique (FR)
- University of Padua (IT)
- Université de Bordeaux (FR)
- European Synchrotron Radiation Facility (FR)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Institut des Maladies Neurodégénératives (FR)
- Vall d'Hebron Institut de Recerca (ES)
- CIC nanoGUNE (ES)
- HM Hospitales (ES)
- University Hospital HM Puerta del Sur (ES)
- Paracelsus Elena Klinik Kassel (DE)
- Synchrotron Radiation for Biomedicine
- University of Göttingen (DE)
- Universidad de Murcia (ES)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Science Advances
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1126/sciadv.adu6050
- Citations
- 4
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 5.56
Funders
- Parkinson's Foundation
- Fondation pour la Recherche Médicale
- Universidad de Murcia
- Ministère de l'Enseignement Supérieur et de la Recherche
- Centre National de la Recherche Scientifique
- Université de Bordeaux
- Association France Parkinson
- Académie des Sciences, Institut de France