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Differential LRRK2 signalling and gene expression in WT-LRRK2 and G2019S-LRRK2 mouse microglia treated with zymosan
Iqra Nazish1, Adamantios Mamais2, Anna Mallach3
1Reta Lila Weston Institute of Neurological Studies and Department of movement neuroscience, UCL Queen Square Institute of Neurology, London WC1N 1PJ.
Introduction:
Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene cause autosomal dominant Parkinson's disease (PD) with the most common causative mutation being the LRRK2 p.G2019S within the kinase domain. LRRK2 protein is highly expressed in the human brain and also in the periphery, and high expression of dominant PD genes in immune cells suggest involvement of microglia and macrophages in inflammation related to PD. LRRK2 is known to respond to extracellular signalling including TLR4 resulting in alterations in gene expression, with the response to TLR2 signalling through zymosan being less known.
Methods:
Here, we investigated the effects of zymosan, a TLR2 agonist and the potent and specific LRRK2 kinase inhibitor MLi-2 on gene expression in microglia from LRRK2-WT and LRRK2 p.G2019S knock-in mice by RNA-Sequencing analysis.
Results:
We observed both overlapping and distinct zymosan and MLi-2 mediated gene expression profiles in microglia. At least two candidate Genome-Wide Association (GWAS) hits for PD, CathepsinB (Ctsb) and Glycoprotein-nmb (Gpnmb), were notably downregulated by zymosan treatment. Genes involved in inflammatory response and nervous system development were up and downregulated respectively with zymosan treatment while MLi-2 treatment particularly exhibited upregulated genes for ion transmembrane transport regulation. Furthermore, we observed the top twenty most significantly differentially expressed genes in LRRK2 p.G2019S microglia show enriched biological processes in iron transport and response to oxidative stress.
Discussion:
Overall, these results suggest that microglial LRRK2 may contribute to PD pathogenesis through altered inflammatory pathways. Our findings should encourage future investigations of these putative avenues in the context of PD pathogenesis.
Insights
Microglial Leucine Rich Repeat Kinase 2 (LRRK2) plays a role in Parkinson's disease (PD) pathogenesis. LRRK2 influences inflammatory pathways and gene expression in microglia, impacting PD development.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) cause autosomal dominant Parkinson's disease (PD).
- LRRK2 is highly expressed in the brain and immune cells like microglia, suggesting a role in PD-related inflammation.
- The impact of TLR2 signaling on LRRK2-mediated gene expression in microglia is not well understood.
Approach:
- Investigated the effects of zymosan (TLR2 agonist) and LRRK2 inhibitor MLi-2 on gene expression in microglia from LRRK2-WT and LRRK2 p.G2019S mice.
- Utilized RNA-Sequencing analysis to compare gene expression profiles.
- Examined overlapping and distinct gene expression patterns induced by zymosan and MLi-2.
Key Points:
- Zymosan treatment downregulated PD GWAS candidates CathepsinB (Ctsb) and Glycoprotein-nmb (Gpnmb).
- Zymosan altered genes involved in inflammatory response and nervous system development.
- LRRK2 p.G2019S microglia showed enriched gene expression related to iron transport and oxidative stress response.
Conclusions:
- Microglial LRRK2 may contribute to Parkinson's disease pathogenesis via altered inflammatory pathways.
- Findings highlight potential therapeutic targets and avenues for future PD research.
- Differential gene expression in LRRK2 p.G2019S microglia suggests specific roles in cellular processes relevant to PD.
