Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice Through Activating TNF‐α Pathway

Abstract

Background Leucine‐rich repeat kinase 2 (LRRK2) is a common risk gene for Parkinson's disease (PD) and inflammatory bowel disorders. However, the penetrance of the most prevalent LRRK2 mutation, G2019S, is <50%. Factors other than genetic mutations are needed in PD process. Objectives To examine whether and how gut inflammation may act as an environmental trigger to neurodegeneration in PD. Methods A mild and chronic dextran sodium sulfate (DSS)‐induced colitis mice model harboring LRRK2 G2019S mutation was established. The colitis severity, immune responses, locomotor function, dopaminergic neuron, and microglia integrity were compared between littermate controls, transgenic LRRK2 wild type (WT), and LRRK2 G2019S mice. Results The LRRK2 G2019S mice are more vulnerable to DSS‐induced colitis than littermate controls or LRRK2 WT animals with increased intestinal expressions of pattern‐recognition receptors, including toll‐like receptors (TLRs), nuclear factor (NF)‐κB activation, and pro‐inflammatory cytokines secretion, especially tumor necrosis factor (TNF)‐α. Notably, the colonic expression of α‐synuclein was significantly increased in LRRK2 G2019S colitis mice. We subsequently observed more aggravated locomotor defect, microglia activation, and dopaminergic neuron loss in LRRK2 G2019S colitis mice than control animals. Treatment with anti‐TNF‐α monoclonal antibody, adalimumab, abrogated both gut and neuroinflammation, mitigated neurodegeneration, and improved locomotor function in LRRK2 G2019S colitis mice. Finally, we validated increased colonic expressions of LRRK2, TLRs, and NF‐κB pathway proteins and elevated plasma TNF‐α level in PD patients compared to controls, especially in those with LRRK2 risk variants. Conclusions Our findings demonstrate that chronic colitis promotes parkinsonism in genetically susceptible mice and TNF‐α plays a detrimental role in the gut‐brain axis of PD. © 2021 International Parkinson and Movement Disorder Society

Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice through Activating TNF‐α Pathway

“…Among subjects with PD, the number of LRRK2-positive cells was higher in those with the LRRK2 genetic risk variants G2385R and R1628P compared with those without LRRK2 mutations. 1 The authors summarize their findings by stating, "Our findings from human participants are supportive of the observations from the LRRK2 G2019S chronic colitis mice." 1 Although we agree with the authors that their findings obtained in human samples are potentially interesting, we would like to draw their attention to a recently published article by our group 2 in which we analyzed LRRK2 expression in the human gastrointestinal tract.…”

“…1 The authors summarize their findings by stating, "Our findings from human participants are supportive of the observations from the LRRK2 G2019S chronic colitis mice." 1 Although we agree with the authors that their findings obtained in human samples are potentially interesting, we would like to draw their attention to a recently published article by our group 2 in which we analyzed LRRK2 expression in the human gastrointestinal tract. In keeping with previous findings obtained in mice, 2 we first showed that the distribution of LRRK2 in the human gastrointestinal tract was not limited to the immune cells but also extended to the two main plexuses of the human enteric nervous system, namely, the submucosal and myenteric plexus 3 (Fig.…”

“…These questions underscore the fact that future research should be conducted to better characterize the expression levels and kinase activity of LRRK2 in the human gastrointestinal tract under physiological conditions, as well as in subjects with idiopathic PD and LRRK2-associated parkinsonism. We are pleased to know that LRRK2 expression is not limited to immune cells in the lamina propria but is also observed in enteric neurons of the submucosal and myenteric plexus of gastrointestinal tracts, as described by Maekawa et al 1 In our recently published study, 2 human colonic tissues were sampled by routine biopsy, which was usually shallow to the level of the submucosal layer, and rarely to the muscular level. Therefore, the LRRK2 expression observed in our routine colonic biopsies was mainly in the lamina propria and did not cover either the submucosal or myenteric plexus.…”

“…These changes in the gastrointestinal tract were associated with parkinsonism features, including locomotor defect, microglia activation, and dopaminergic neuron loss in the central nervous system. 1 To reinforce the findings obtained in mice, the authors performed a set of additional experiments with human samples. The expression of LRRK2 was analyzed by immunohistochemistry in colonic biopsies from 19 patients with PD (7 with LRRK2 genetic variants G2385R or R1628P, 12 without LRRK2 mutations) and 7 age-matched controls.…”

“…With interest, we read the article by Lin et al 1 on the possible role of LRRK2 and gut inflammation in the development of Parkinson's disease (PD). Using a transgenic mouse model overexpressing the G2019S mutation of the human LRRK2 gene, they showed that transgenic animals are more vulnerable to Dextran sodium sulfate-induced colitis than control littermates with gut hyperpermeability and an increased intestinal expression of pattern recognition receptors.…”