Parkinson's disease can be considered the prototypical neurodegenerative disease of the gut-brain axis. Indeed, lesions similar to those observed in the central nervous system (alpha-synuclein deposits) are present in the enteric nervous system in the vast majority of people with Parkinson's disease, and digestive disorders (constipation, gastric fullness, etc.) are common during the course of the disease. It is proposed that the digestive tract and the enteric nervous system play a role in the initiation and development of the disease. Our team was the first to show that it was possible to detect alpha-synuclein deposits in enteric neurons from a simple digestive biopsy opening the way to a histopathological diagnosis of the disease during the patient's lifetime. We later showed that the lesion load of alpha-synuclein in digestive biopsies was related to the severity of Parkinson's disease. Our current project aims to better understand the digestive damage during the disease by focusing not only on enteric neurons but also on enteric glial cells and intestinal epithelial cells. The IBIMPark project (Laurène Leclair, principal investigator) studies inflammation and digestive permeability in early Parkinson's disease using digestive biopsies. Sébastien Paillusson is studying the physiological role of endoplasmic reticulum membranes associated with mitochondria in enteric neurons and their possible role in the enteric neuropathy of Parkinson's disease. Our third project focuses on the regulation of the expression in enteric neurons and glia of the LRRK2 protein that is involved in familial forms of Parkinson's disease.
Figure 1. cell types that can be analyzed using a routine gastrointestinal biopsy. Biopsy forceps used for routine GI biopsies are capable of capturing intestinal epithelial cells as well as enteric glial cells (EGCs) and neuron extensions present in the mucosa. Biopsies also allow access to EGCs and cell bodies of submucosal plexus neurons (SMP). Expression levels and distribution of neuronal markers such as 220 kDa neurofilament heavy chain protein (NF-220), enteric glial markers such as S100-b and tight junction proteins such as occludin can be analyzed by immunohistochemistry. MM: mucosal muscularis; MP: myenteric plexus; SMP: submucosal plexus. This figure was created in part by Servier Medical Art under a Creative Commons Attribution 3.0 Unported License.
Figure 2. Analyses that can be performed from a single colonic biopsy. 1) The biopsy can be transferred to a Sylgard-coated Petri dish for microdissection under a stereomicroscope. The submucosa is then mechanically separated from the mucosa and the expression levels and distribution of neuronal markers such as NF-220, enteric glial markers such as S100-b and tight junction proteins such as ZO-1 can be analyzed by immunohistochemistry. 2) The biopsy can be frozen for further analysis by PCR, 1D and 2D electrophoresis. The illustration shows a 2D GFAP immunoblot performed using lysates from 2 pooled colonic biopsies (control subject). 3) The fresh biopsy can be mounted in Ussing chambers for ex vivo analysis of intestinal permeability. This figure was created in part using Servier Medical Art, under a Creative Commons Attribution 3.0 Unported License.
Researchers / Clinicians
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Lebouvier T, Neunlist M, Bruley des Varannes S, Coron E, Drouard A, N'Guyen JM, Chaumette T, Tasselli M, Paillusson S, Flamand M, Galmiche JP, Damier P, Derkinderen P. Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms. PLoS One. 2010 Sep 14;5(9):e12728. Link
Leclair-Visonneau L, Clairembault T, Coron E, Le Dily S, Vavasseur F, Dalichampt M, Péréon Y, Neunlist M, Derkinderen P. REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease. Neurology. 2017 Oct 10;89(15):1612-1618. Link
de Guilhem de Lataillade A, Verchere J, Oullier T, Prigent A, Durand T, Pellegrini C, Neunlist M, Baron T, Rolli-Derkinderen M, Derkinderen P. LRRK2 is reduced in Parkinson's disease gut. Acta Neuropathol. 2021 Sep;142(3):601-603. Link