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

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.

Automated summary

The LRRK2 gene is associated with both Parkinson's disease (PD) and Crohn's disease, suggesting its role in gastrointestinal inflammation. However, there is limited research on LRRK2 in the enteric nervous system (ENS). This study characterizes LRRK2 expression in the ENS, revealing its presence in enteric glial cells and identifying the cAMP pathway as a key regulator of LRRK2 expression in these cells. The findings provide a basis for further understanding the functions of LRRK2 in the ENS and investigating pathological changes in enteric synucleinopathies.