Up-regulation of the kinase LRRK2, in enteric glia contributes to mucosal barrier impairment in Parkinson's disease via secretory autophagy.
Up-regulation of the kinase LRRK2, in enteric glia contributes to mucosal barrier impairment in Parkinson's disease via secretory autophagy.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Pisa, IT · Author affiliation
Unit of Human Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.Location evidence
Florence, IT · Author affiliation
Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section, University of Florence, Florence, Italy.Location evidence
Nantes, FR · Author affiliation
Nantes Université, CHU Nantes, Nantes, France.Location evidence
MT · Author affiliation · country only
Department of Health Sciences, United Campus of Malta, Msida, Malta.Location evidence
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Original abstract
BACKGROUND AND PURPOSE: 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). EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: These changes could influence bowel symptoms and central pathology associated with PD, via the gut-brain axis.