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<p>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.</p>

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Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月5日

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  • 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,
  • Benjamin Dehay,
  • Miquel Vila,
  • Javier Vitorica,
  • Francisco Pérez-Sánchez,
  • Isabel Fariñas

摘要

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.