PXD069218

PXD069218 is an original dataset announced via ProteomeXchange.

Title	Intestinal Macrophages Modulate Brain Synucleinopathy in Parkinson’s disease
Description	Emerging evidence suggests that Parkinson’s disease (PD) may have its origin in the enteric nervous system (ENS), from where alpha-synuclein (αS) pathology spreads to the brain. Decades before the onset of motor symptoms, PD patients suffer from constipation and present with circulating T cells that are responsive to αS, suggesting that peripheral immune responses in the ENS may be involved in early stages of PD. However, cellular mechanisms that trigger αS pathology in the ENS and its spread along the gut-brain axis remain elusive. Here, we demonstrate that muscularis macrophages (ME-Macs), housekeepers of ENS integrity and intestinal homeostasis, modulate αS pathology in models of PD. ME-Macs contain misfolded αS, adopt a signature that reflects endolysosomal dysfunction and modulate expansion of T cells that travel from the ENS to the brain via dura mater as αS pathology progresses. Directed ME-Mac depletion leads to reduced αS pathology in the ENS and CNS, prevents T cell expansion and mitigates motor dysfunction, suggesting a role for ME-Macs as early cellular initiators of αS pathology along the gut-brain axis. Understanding these mechanisms could pave the way for early-stage biomarkers in PD.
HostingRepository	PRIDE
AnnounceDate	2026-03-09
AnnouncementXML	Submission_2026-03-08_17:23:16.759.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bethany Geary
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-08 15:03:26	ID requested
⏵ 1	2026-03-08 17:23:18	announced

De Schepper S, Konstantellos V, Conway JA, Sokolova D, Zaccagnini L, Cowley MV, Sierksma A, Yudina M, Edmonds M, Gavriouchkina D, Geary B, Wallis A, Celikag M, Baykam Z, Vara-P, é, rez M, Crowley G, Hager FT, Bijnen M, Posner D, Luk K, Cerovic V, Clatworthy M, Videlock EJ, Jaunmuktane Z, Movahedi K, Greter M, Chain B, Alessi DR, Hong S, Bartels T, Intestinal macrophages modulate synucleinopathy along the gut-brain axis. Nature, 651(8104):174-184(2026) [pubmed]

10.1038/s41586-025-09984-y;

submitter keyword: alpha-synuclein,Parkinson's disease, DIA, macrophages

Sebastiaan De Schepper
contact affiliation	UK Dementia Research Institute
contact email	sebastiaan.deschepper@uantwerpen.be
lab head
Bethany Geary
contact affiliation	UK Dementia Research Institute
contact email	beth.geary@ukdri.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/03/PXD069218

PRIDE project URI

• PRIDE
  1. PXD069218
     1. Label: PRIDE project
     2. Name: Intestinal Macrophages Modulate Brain Synucleinopathy in Parkinson’s disease