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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, UK.
Abstract:
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 suggests 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. 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. 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 that 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. 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
Mutations in leucine-rich repeat kinase 2 (LRRK2) influence Parkinson's disease (PD) pathogenesis. This study reveals how LRRK2 in microglia affects gene expression in response to inflammatory signals, impacting PD development.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of autosomal dominant Parkinson's disease (PD).
- LRRK2 is expressed in immune cells like microglia, suggesting a role in PD-related neuroinflammation.
- The response of LRRK2 to TLR2 signaling via zymosan in microglia is not well understood.
Purpose of the Study:
- To investigate the effects of zymosan (a TLR2 agonist) and an LRRK2 inhibitor (MLi-2) on microglial gene expression.
- To compare gene expression profiles in microglia from wild-type (WT) and LRRK2 p.G2019S knock-in mice.
Main Methods:
- Utilized RNA-sequencing analysis to examine gene expression changes in microglia.
- Treated microglia with zymosan and MLi-2, a specific LRRK2 kinase inhibitor.
Main Results:
- Observed distinct and overlapping gene expression patterns induced by zymosan and MLi-2.
- Zymosan downregulated Parkinson's disease GWAS hits (Ctsb, Gpnmb) and genes involved in nervous system development.
- MLi-2 upregulated genes related to ion transmembrane transport; LRRK2 p.G2019S microglia showed enrichment in iron transport and oxidative stress response genes.
Conclusions:
- Microglial LRRK2 activity influences gene expression related to inflammation and cellular processes relevant to PD.
- These findings highlight potential therapeutic targets involving LRRK2 modulation in Parkinson's disease pathogenesis.
