Dataset Information

Intestinal Macrophages Modulate Brain Synucleinopathy in Parkinson’s disease

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Macrophage

SUBMITTER: Bethany Geary

LAB HEAD: Sebastiaan De Schepper

PROVIDER: PXD069218 | Pride | 2026-03-09

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20220131_BG_X009_D1_165166167.raw	Raw
	20220131_BG_X009_D1_168169170.raw	Raw
	20220131_BG_X009_DIANN_report.pg_matrix.tsv	Tabular
	20220131_BG_X009_ML.raw	Raw
	20220131_BG_X009_UN_172174175.raw	Raw

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Publications

Intestinal macrophages modulate synucleinopathy along the gut-brain axis.

De Schepper Sebastiaan S Konstantellos Viktoras V Conway James A JA Sokolova Dimitra D Zaccagnini Ludovica L Cowley Matthew V MV Sierksma Annerieke A Yudina Maria M Edmonds Marisa M Gavriouchkina Daria D Geary Bethany B Wallis Amber A Celikag Meral M Baykam Zeynep Z Vara-Pérez Mónica M Crowley Gerard G Hager Fabian Tobias FT Bijnen Mitchell M Posner David D Luk Kelvin K Cerovic Vuk V Clatworthy Menna M Videlock Elizabeth J EJ Jaunmuktane Zane Z Movahedi Kiavash K Greter Melanie M Chain Benny B Alessi Dario R DR Hong Soyon S Bartels Tim T

Nature 20260128

Emerging evidence suggests that Parkinson's disease (PD) may have its origin in the enteric nervous system (ENS), from where α-synuclein (αS) pathology spreads to the brain<sup>1-4</sup>. Decades before the onset of motor symptoms, patients with PD suffer from constipation and present with circulating T cells responsive to αS, suggesting that peripheral immune responses initiated in the ENS may be involved in the early stages of PD<sup>1,5-7</sup>. However, cellular mechanisms that trigger αS pa ...[more]

PMID: 41606336

Similar Datasets

Project description:Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (αsyn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote αsyn spread or drive the generation of highly pathogenic αsyn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human α-syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several αsyn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-αsyn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granular layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, and this might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we permed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dctn2 interaction was shared across all PFF conditions, and Nckap1 and Ap3b2 were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and αsyn strain had little effect on overall seeding efficacy and global PSER129-interactions.