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Peer-reviewedCC BYThe Journal of experimental medicine

Cerebrospinal fluid and dural accumulation of α-synuclein impairs CNS clearance in Parkinson's disease.

  • Taylor J Stevenson1,2
  • Luca Vinnell1,2
  • Samuel J C McCullough1,2
  • Daniel X Flyger1,2
  • Blake Highet2,3
  • James A Wiseman2,3
  • Ben Watkin1,2
  • Kate Hitpass Romero1,2
  • Victoria F Low2,3
  • Amy M Smith1,2
  • Angela Wu1,2
  • Dahna M Fong1,2
8 more authors
  • Natasha L Grimsey1,2
  • Birger V Dieriks2,3
  • Clinton P Turner4
  • Deborah Young1,2
  • Maurice A Curtis2,3
  • Richard L M Faull2,3
  • Mike Dragunow1,2
  • Justin Rustenhoven1,2
4 affiliations
  1. 1Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand.
  2. 2Centre for Brain Research, The University of Auckland , Auckland, New Zealand.
  3. 3Department of Anatomy and Medical Imaging, The University of Auckland, Auckland, New Zealand.
  4. 4LabPlus, Department of Anatomical Pathology, Te Whatu Ora, Auckland, New Zealand.
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Abstract

Parkinson's disease (PD) is characterized by the build-up of α-synuclein (α-syn) in the brain, where it drives neurodegeneration. Importantly, aggregated α-syn also accumulates in the cerebrospinal fluid (CSF) of PD patients, and while increasingly used for diagnosis, its pathological role remains poorly understood. Here, we demonstrate that α-syn accumulation in central nervous system (CNS) border tissues promotes CNS clearance deficits, as observed in PD patients. We find that aggregated α-syn accumulates not only in the CSF but also in the dura mater of individuals with PD, and, using acute and chronic mouse models, show that α-syn deposition in these sites induces immune alterations in CNS borders and disrupts CNS clearance. Mechanistically, we reveal that α-syn at CNS borders elevates CSF TNF and demonstrate that both TNF and α-syn aggregates themselves impair lymphatic endothelial cell function. These findings demonstrate a pathological role for α-syn in the CNS border tissues and position meningeal immunity as a contributor to CNS clearance deficits in PD pathogenesis.

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Cite

BibTeXRIS
BibTeX
@article{stevenson2026cerebrospinal,
  title = {{Cerebrospinal fluid and dural accumulation of α-synuclein impairs CNS clearance in Parkinson's disease.}},
  author = {Taylor J Stevenson and Luca Vinnell and Samuel J C McCullough and Daniel X Flyger and Blake Highet and James A Wiseman and Ben Watkin and Kate Hitpass Romero and Victoria F Low and Amy M Smith and Angela Wu and Dahna M Fong and Natasha L Grimsey and Birger V Dieriks and Clinton P Turner and Deborah Young and Maurice A Curtis and Richard L M Faull and Mike Dragunow and Justin Rustenhoven},
  journal = {The Journal of experimental medicine},
  year = {2026},
  month = oct,
  doi = {10.1084/jem.20251245},
  url = {https://europepmc.org/article/MED/42900184},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Cerebrospinal fluid and dural accumulation of α-synuclein impairs CNS clearance in Parkinson's disease.
AU  - Taylor J Stevenson
AU  - Luca Vinnell
AU  - Samuel J C McCullough
AU  - Daniel X Flyger
AU  - Blake Highet
AU  - James A Wiseman
AU  - Ben Watkin
AU  - Kate Hitpass Romero
AU  - Victoria F Low
AU  - Amy M Smith
AU  - Angela Wu
AU  - Dahna M Fong
AU  - Natasha L Grimsey
AU  - Birger V Dieriks
AU  - Clinton P Turner
AU  - Deborah Young
AU  - Maurice A Curtis
AU  - Richard L M Faull
AU  - Mike Dragunow
AU  - Justin Rustenhoven
PY  - 2026
DA  - 2026/10/20
JO  - The Journal of experimental medicine
DO  - 10.1084/jem.20251245
UR  - https://europepmc.org/article/MED/42900184
AB  - Parkinson's disease (PD) is characterized by the build-up of α-synuclein (α-syn) in the brain, where it drives neurodegeneration. Importantly, aggregated α-syn also accumulates in the cerebrospinal fluid (CSF) of PD patients, and while increasingly used for diagnosis, its pathological role remains poorly understood. Here, we demonstrate that α-syn accumulation in central nervous system (CNS) border tissues promotes CNS clearance deficits, as observed in PD patients. We find that aggregated α-syn accumulates not only in the CSF but also in the dura mater of individuals with PD, and, using acute and chronic mouse models, show that α-syn deposition in these sites induces immune alterations in CNS borders and disrupts CNS clearance. Mechanistically, we reveal that α-syn at CNS borders elevates CSF TNF and demonstrate that both TNF and α-syn aggregates themselves impair lymphatic endothelial cell function. These findings demonstrate a pathological role for α-syn in the CNS border tissues and position meningeal immunity as a contributor to CNS clearance deficits in PD pathogenesis.
SN  - 0022-1007
SN  - 1540-9538
ER  -