Parkinson’s disease is a neurodegenerative disease that affects the central nervous system, causing involuntary movements such as tremors, stiffness and difficulty with balance and coordination. It is characterised by the loss of neurons that produce dopamine, a neurotransmitter essential for the proper functioning of the neural circuits that control movement.

Although the exact cause of the disease remains unknown, Parkinson’s patients exhibit abnormal accumulations of the protein alpha-synuclein — known as Lewy bodies. The neuronal damage caused by the abnormal spread of alpha-synuclein in the brain may explain why the disease progresses over time. However, the exact mechanism behind this propagation is still unknown.

A study led by professor of Cell Biology Isabel Fariñas (recipient of the 2024 National Research Award), head of the Molecular Neurobiology Unit at the BIOTECMED Institute of the University of Valencia, has just provided new insights into this field of research. The team has revealed the crucial role of microglia — the most abundant immune cells in the central nervous system — in the spread of the disease, and their findings have been published in the journal Molecular Neurodegeneration.

Microglial cells act as the brain’s defence system, clearing and breaking down toxic accumulations of alpha-synuclein. However, according to the study, microglia play a dual role in this process. In a young brain, these cells effectively destroy and remove toxic alpha-synuclein aggregates, protecting the brain. However, as we age, microglia lose their efficiency, which means that instead of eliminating the protein, they may contribute to its accumulation and spread. “When we injected Lewy bodies isolated from Parkinson’s patients into young and aged mice, we observed that aged microglia were not only unable to degrade them efficiently but also favoured the spread of toxic alpha-synuclein to nearby neurons”, explains Salomé Sirerol, a researcher at BIOTECMED and one of the study’s lead authors.

The findings of this study, conducted in mouse models and tested in human tissue samples from Parkinson’s patients, open the door to new therapeutic strategies. “Enhancing the microglia’s ability to efficiently clear abnormal alpha-synuclein as we age could become a promising approach to slowing the progression of Parkinson’s”, suggests Isabel Fariñas, the study’s lead investigator.

The research was carried out by a team from BIOTECMED and the Department of Cell Biology, Functional Biology and Physical Anthropology of the UV, in collaboration with the Catholic University of Valencia, the Institute of Neurosciences of the San Carlos Clinical Hospital in Madrid, the University of Bordeaux, the Institute of Biomedicine of Seville and the Vall d’Hebron Research Institute in Barcelona.

Reference:
Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species.
Mª Salomé Sirerol-Piquer, Ana Perez-Villalba, Pere Duart-Abadia, Germán Belenguer, Ulises Gómez-Pinedo, Laura Blasco-Chamarro, Pau Carrillo-Barberà, Azucena Pérez-Cañamás, Victoria Navarro-Garrido, Miquel Vila, Javier Vitorica, Francisco Pérez-Sánchez and Isabel Fariñas. Molecular Neurodegeneration, vol. 20, 2025.