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

• Published in: Movement disorders Vol. 37; no. 4; pp. 745 - 757
• Main Authors: Lin, Chin‐Hsien, Lin, Han‐Yi, Ho, En‐Pong, Ke, Yi‐Ci, Cheng, Mei‐Fang, Shiue, Chyng‐Yann, Wu, Chi‐Han, Liao, Peng‐Hsiang, Hsu, Angela Yu‐Huey, Chu, Li‐An, Liu, Ya‐Ding, Lin, Ya‐Hui, Tai, Yi‐Cheng, Shun, Chia‐Tung, Chiu, Han‐Mo, Wu, Ming‐Shiang
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.04.2022; Wiley Subscription Services, Inc
• Subjects: Animals; Animals, Genetically Modified; Basal ganglia; Brain diseases; Central nervous system diseases; Colitis; Colitis - chemically induced; Colitis - complications; Colitis - genetics; Dextran; Digestive system; Dopamine receptors; Gastrointestinal tract; Gut-brain axis; Humans; Immune response; Inflammatory bowel disease; Inflammatory diseases; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; LRRK2 protein; Mice; Mice, Transgenic; Microglia; Monoclonal antibodies; Movement disorders; Mutation; Mutation - genetics; Neurodegeneration; Neurodegenerative diseases; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Parkinson's diseasegut inflammationinflammatory bowel diseasegut‐brain axisleucine‐rich repeat kinase 2tumor necrosis factor‐alpha; Parkinsonian Disorders - genetics; Sodium sulfate; Synuclein; Tumor necrosis factor; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tumor necrosis factor-TNF; Parkinson's diseasegut inflammationinflammatory bowel diseasegut-brain axisleucine-rich repeat kinase 2tumor necrosis factor-alpha
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.28890

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