LRRK2^R1627P mutation amplifies environmental risk factors induced chronic inflammation and α-synuclein aggregation in the gut of rats

Area of Science:

• Neuroscience
• Gastroenterology
• Genetics

Background:

• Chronic intestinal inflammation is a known precursor to Parkinson's disease (PD).
• The Leucine-rich repeat kinase 2 R1628P variant (LRRK2^R1628P) is a risk factor for PD in Asian populations.
• The role of LRRK2^R1628P in driving intestinal inflammation is not well understood.

Purpose of the Study:

• To investigate the impact of the LRRK2^R1627P variant (rat homolog) on intestinal homeostasis during aging and in response to toxin exposure.
• To elucidate the underlying mechanisms by which LRRK2^R1627P contributes to PD-associated intestinal pathology.
• To assess the therapeutic potential of targeting the TLR4 pathway.

Main Methods:

• Utilized LRRK2^R1627P rats and wild-type rats for comparative studies.
• Analyzed intestinal morphology, epithelial cell junctions, and macrophage polarization.
• Investigated the TLR4/MyD88/NF-κB signaling pathway.
• Assessed the effects of lipopolysaccharide (LPS) and a TLR4 inhibitor.

Main Results:

• Aging LRRK2^R1627P rats displayed shortened small intestines, reduced goblet cells, and disrupted epithelial junctions.
• LRRK2^R1627P induced macrophage polarization towards a pro-inflammatory phenotype via the TLR4/MyD88/NF-κB pathway.
• This resulted in PD-associated intestinal pathology, including chronic inflammation, decreased microbial diversity, and increased p-α-synuclein aggregation.
• LRRK2^R1627P exacerbated LPS-induced intestinal inflammation, which was ameliorated by a TLR4 inhibitor.

Conclusions:

• The LRRK2^R1627P variant disrupts intestinal homeostasis, exacerbates inflammation, and promotes PD pathology in aging rats.
• The TLR4/MyD88/NF-κB pathway is a key mediator of LRRK2^R1627P-induced intestinal dysfunction.
• Targeting TLR4 offers a potential therapeutic strategy for mitigating LRRK2^R1627P-associated PD pathology.