Up-regulation of the kinase LRRK2, in enteric glia contributes to mucosal barrier impairment in Parkinson's disease via secretory autophagy.

Authors

Vanessa D'Antongiovanni, Clarissa Pierucci, Cristina Segnani, Chiara Ippolito, Clelia Di Salvo, Elena Lucarini, Luca Antonioli, Matteo Fornai, Nunzia Bernardini, Pascal Derkinderen, Carmelo Scarpignato, Carolina Pellegrini

Published in

British journal of pharmacology. Aug 13, 2026. Epub Aug 13, 2026.

Abstract

Patients with Parkinson's disease (PD) show intestinal epithelial barrier (IEB) alterations, enteric gliosis and inflammation that could contribute to gastrointestinal symptoms. Moreover, changes in leucine rich-repeat kinase 2 (LRRK2) expression/activity have been associated with PD development and related intestinal inflammation. However, the molecular determinants linking LRRK2, enteric gliosis and IEB impairment remain unclear. Therefore, we investigated the role of LRRK2 in IEB changes associated with PD, focusing on its role in the interplay between enteric glial cells (EGCs) and intestinal epithelial cells (IECs).
Human A53T α-synuclein transgenic (Tg) mice (9 months old) were provided a model of early PD. Central neuroinflammation was studied by IBA-1 staining. Intestinal motility, colonic α-synuclein and LRRK2 expression were assessed. Enteric gliosis was evaluated by detection of GFAP⁺ cells co-expressing LRRK2; IEB was tested by mucins detection and quantification of Muc-2, tight junction proteins and secretory autophagy. In vitro co-cultures between EGCs and IECs were performed to investigate glial LRRK2-mediated gut barrier alterations.
A53T mice, without central neuroinflammation, showed intestinal disturbances, colonic α-synuclein accumulation and an increase in colonic GFAP⁺/LRRK2⁺ glial cells before brain pathology. Moreover, PD animals displayed IEB alterations and increased colonic autophagosomes, suggesting a shift towards secretory autophagy. In co-culture experiments, α-synuclein and lipopolysaccharide promoted enteric gliosis and LRRK2 up-regulation in glial cells, contributing to IEB impairment via secretory autophagy.
These changes could influence bowel symptoms and central pathology associated with PD, via the gut-brain axis.

PMID:
42593416
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.

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