LRRK2 expression in normal and pathologic human gut and in rodent enteric neural cell lines

• Published in: Journal of neurochemistry 2023-01, Vol.164 (2), p.193-209
• Main Authors: de Guilhem de Lataillade, Adrien, Caillaud, Martial, Oullier, Thibauld, Naveilhan, Philippe, Pellegrini, Carolina, Tolosa, Eduardo, Neunlist, Michel, Rolli‐Derkinderen, Malvyne, Gelpi, Ellen, Derkinderen, Pascal
• Format: Article
• Language: English
• Subjects: Adult; Animals; Biopsy; Cell Line; Cell lines; Central nervous system; Crohn Disease; Crohn Disease - metabolism; Crohn Disease - pathology; Crohn's disease; cyclic AMP; Disorders; enteric glial cell; Enteric Nervous System; Enteric Nervous System - metabolism; enteric neuron; Fetuses; Ganglia; Glial cells; Humans; Immune system; Immunofluorescence; Kinases; Leucine; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; Lewy bodies; Life Sciences; LRRK2; LRRK2 protein; Movement disorders; Myenteric plexus; Nervous system; Neurodegenerative diseases; Neuroglia; Neuronal-glial interactions; Neurons; Neurons - metabolism; Parkinson Disease; Parkinson Disease - metabolism; Parkinson's disease; Phosphorylation; Signal transduction
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15704

Leucine‐rich repeat kinase 2 (LRRK2) gene, which is the gene most commonly associated with Parkinson's disease (PD), is also a susceptibility gene for Crohn's disease, thereby suggesting that LRRK2 may sit at the crossroads of gastrointestinal inflammation, Parkinson's, and Crohn's disease. LRRK2 protein has been studied intensely in both CNS neurons and in immune cells, but there are only few studies on LRRK2 in the enteric nervous system (ENS). LRRK2 is present in ENS ganglia and the existing studies on LRRK2 expression in colonic biopsies from PD subjects have yielded conflicting results. Herein, we propose to extend these findings by studying in more details LRRK2 expression in the ENS. LRRK2 expression was evaluated in full thickness segments of colon of 16 Lewy body, 12 non‐Lewy body disorders cases, and 3 non‐neurodegenerative controls and in various enteric neural cell lines. We showed that, in addition to enteric neurons, LRRK2 is constitutively expressed in enteric glial cells in both fetal and adult tissues. LRRK2 immunofluorescence intensity in the myenteric ganglia was not different between Lewy body and non‐Lewy body disorders. Additionally, we identified the cAMP pathway as a key signaling pathway involved in the regulation of LRRK2 expression and phosphorylation in the enteric glial cells. Our study is the first detailed characterization of LRRK2 in the ENS and the first to show that enteric glial cells express LRRK2. Our findings provide a basis to unravel the functions of LRRK2 in the ENS and to further investigate the pathological changes in enteric synucleinopathies. We show that leucine‐rich repeat kinase 2 (LRRK2) is constitutively expressed in enteric neurons and glial cells in both fetal and adult tissues (1 and 3). The expression levels of LRRK2 in the myenteric plexus were not different between subjects with Lewy body (LB) and non‐Lewy body (non‐LB) disorders (2). Additionally, we identified the cAMP pathway as a key signaling pathway involved in regulation of LRRK2 expression in enteric neurons and glial cells (3). Our findings provide a basis to unravel the functions of LRRK2 in the gut and to further investigate the pathological changes in enteric synucleinopathies.