Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice Through Activating TNF-α Pathway
Chin-Hsien Lin1, Han-Yi Lin1, En-Pong Ho1
1Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
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.
Insights
Gut inflammation can trigger Parkinson's disease (PD) in individuals with LRRK2 mutations. Blocking TNF-α reduces neuroinflammation and improves motor function, highlighting a gut-brain axis target for PD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Leucine-rich repeat kinase 2 (LRRK2) is a significant genetic risk factor for Parkinson's disease (PD).
- The penetrance of common LRRK2 mutations, like G2019S, is incomplete, suggesting environmental factors contribute to PD pathogenesis.
- Gut inflammation is increasingly recognized as a potential environmental trigger in neurodegenerative diseases.
Purpose of the Study:
- To investigate if gut inflammation acts as an environmental trigger for neurodegeneration in Parkinson's disease.
- To elucidate the role of the LRRK2 G2019S mutation in susceptibility to colitis-induced neuroinflammation.
- To assess the therapeutic potential of targeting TNF-α in a mouse model of PD and gut inflammation.
Main Methods:
- Established a dextran sodium sulfate (DSS)-induced colitis mouse model in mice with the LRRK2 G2019S mutation.
- Compared colitis severity, immune responses, locomotor function, and dopaminergic neuron integrity between LRRK2 G2019S, LRRK2 wild-type (WT), and control mice.
- Administered anti-TNF-α monoclonal antibody (adalimumab) to assess its effects on gut and neuroinflammation, neurodegeneration, and motor function.
Main Results:
- LRRK2 G2019S mice exhibited heightened vulnerability to DSS-induced colitis, with increased intestinal pro-inflammatory markers (TLRs, NF-κB, TNF-α) and colonic α-synuclein expression.
- Colitis in LRRK2 G2019S mice led to exacerbated locomotor deficits, microglial activation, and dopaminergic neuron loss.
- Adalimumab treatment successfully abrogated gut and neuroinflammation, mitigated neurodegeneration, and improved locomotor function in LRRK2 G2019S colitis mice.
- Elevated colonic LRRK2, TLRs, NF-κB pathway proteins, and plasma TNF-α were observed in PD patients, particularly those with LRRK2 risk variants.
Conclusions:
- Chronic gut inflammation promotes parkinsonism in genetically susceptible LRRK2 G2019S mice.
- Tumor necrosis factor-alpha (TNF-α) plays a critical detrimental role in the gut-brain axis in Parkinson's disease.
- Targeting TNF-α represents a promising therapeutic strategy for Parkinson's disease, particularly in individuals with LRRK2 mutations and gut inflammation.
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