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

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.

Early Dysbiosis and Dampened Gut Microbe Oscillation Precede Motor Dysfunction and Neuropathology in Animal Models of Parkinson's Disease.

BACKGROUND: Studies have shown different gut microbiomes in patients with Parkinson's disease (PD) compared to unaffected controls. However, when the gut microbiota shift toward dysbiosis in the PD process remains unclear. OBJECTIVE: We aim to investigate the changes in gut microbiota, locomotor function, and neuropathology longitudinally in PD rodent models. METHODS: Fecal microbiota were longitudinally assessed by sequencing the V4-V5 region of the 16S ribosomal RNA gene in a human mutant α-synuclein over-expressing mouse model of PD, SNCA p.A53T mice, and the non-transgenic littermate controls. The locomotor function, neuronal integrity, and α-synuclein expression in the different brain regions were compared between groups. Human fecal microbiota communities from 58 patients with PD and 46 unaffected controls were also analyzed using metagenomic sequencing for comparison. RESULTS: Compared to non-transgenic littermate controls, the altered gut microbiota of the SNCA p.A53T mice can be detected as early as 2 months old, and the diurnal oscillation of the gut microbiome was dampened throughout PD progression starting from 4 months old. However, neuropathology changes and motor deficits were observed starting at 6 months old. Similar changes in altered gut microbiota were also observed in another PD genetic mouse model carrying the LRRK2 p.G2019S mutation at 2 months old. Among the commonly enriched gut microbiota in both PD genetic mouse models, the abundance of Parabateroides Merdae and Ruminococcus torques were also increased in human PD patients compared to controls. CONCLUSION: These findings revealed the altered gut microbiota communities and oscillations preceding the occurrence of neuropathy and motor dysfunction in the PD process.