Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species
Cytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson's disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic reaction of microglia to toxic forms of αSyn remains elusive, which is especially relevant considering the recently uncovered microglial molecular diversity. Here, we show that periventricular microglia of the subependymal neurogenic niche monitor the cerebrospinal fluid and can rapidly phagocytize and degrade different aggregated forms of αSyn delivered into the lateral ventricle. However, this clearing ability worsens with age, leading to an increase in microglia with aggregates in aged treated mice, an accumulation also observed in human PD samples. We also show that exposure of aged microglia to aggregated αSyn isolated from human PD samples results in the phosphorylation of the endogenous protein and the generation of αSyn seeds that can transmit the pathology to healthy neurons. Our data indicate that while microglial phagocytosis rapidly clears toxic αSyn, aged microglia can contribute to synucleinopathy spreading.
Authors
- Benjamin Dehay (ORCID: https://orcid.org/0000-0003-1723-9045)
- Pau Carrillo-Barberà (ORCID: https://orcid.org/0000-0002-6214-6238)
- Victoria Navarro (ORCID: https://orcid.org/0000-0002-4385-9697)
- Pere Duart-Abadía (ORCID: https://orcid.org/0000-0003-1033-121X)
- Ana Pérez‐Villalba (ORCID: https://orcid.org/0000-0002-5330-2374)
- Azucena Pérez‐Cañamás (ORCID: https://orcid.org/0000-0003-3635-6298)
- Miquel Vila (ORCID: https://orcid.org/0000-0002-1352-989X)
- Isabel Fariñas (ORCID: https://orcid.org/0000-0003-2903-4960)
- Javier Vitórica (ORCID: https://orcid.org/0000-0002-0641-7902)
- Laura Blasco-Chamarro (ORCID: https://orcid.org/0000-0002-5902-6120)
- Ma Salomé Sirerol-Piquer (ORCID: https://orcid.org/0000-0002-9678-4502)
- Francisco Pérez‐Sánchez (ORCID: https://orcid.org/0000-0002-4320-640X)
- Germán Belenguer (ORCID: https://orcid.org/0000-0002-8687-271X)
- Ulises Gómez-Pinedo
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universidad Complutense de Madrid (ES)
- Universitat Autònoma de Barcelona (ES)
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Universitat de València (ES)
- Valencia Catholic University Saint Vincent Martyr (ES)
- Hospital Clínico San Carlos (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Institut des Maladies Neurodégénératives (FR)
- Vall d'Hebron Institut de Recerca (ES)
- Centro de Investigación Biomédica en Red (ES)
- Instituto de Biomedicina de Sevilla (ES)
- Universidad de Sevilla (ES)
Publication Details
- Journal
- Molecular Neurodegeneration
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1186/s13024-025-00816-1
- Citations
- 10
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 13.89
Funders
- Generalitat Valenciana
- Ministerio de Ciencia e Innovación
- Université de Bordeaux
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana