Genome-wide analysis of LPS-responsive gene expression by microglia cells in Ntg and LRRK2KO mouse brain
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Lixin Sun
PROVIDER: E-GEOD-83562 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Analysis of LRRK2-regulation of microglia responce to the LPS at gene expression level. The hypothesis tested in the present study was whether LRRK2 influence the microglial phagocytosis- and neuroinflammation- related gene expression at mRNA level.
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Project description:BACKGROUND: Previous data implicates neuroinflammation in the pathogenesis of Parkinson’s disease (PD). Of the genes associated with PD, Leucine rich repeat kinase 2 (LRRK2) is expressed in microglia, resident brain inflammatory cells. However, the extent to which LRRK2 affects neuroinflammatory responses is unclear. OBJECTIVE: To examine whether mutations in Lrrk2 affect responses to neuroinflammation in vivo. METHODS: We injected cohorts of mice carrying mutations in Lrrk2, homologous to those causing human PD, with a single intrastriatal injection of lipopolysaccharide (LPS) or control. We used single cell RNA-Sequencing to examine cell type specific responses to treatment and genotype and validated key results with orthogonal approaches. RESULTS: We found that our chosen paradigm of acute LPS exposure evokes robust transcriptional changes consistent with a multicellular neuroinflammatory response. We also found evidence of peripheral immune cell recruitment into the brain and interaction with brain-resident microglia. However, the transcriptional effects of Lrrk2 mutations were limited to small numbers of genes, including down regulation of gene ontogeny terms related to lysosomes, predominantly in microglia. CONCLUSIONS: Our data clearly demonstrate that many cells in the brain respond to a single inflammatory insult with strong transcriptional responses and that, even in a model focussed on CNS injection, there is interaction between peripheral and central immune cells. In contrast, the quantitative effects of Lrrk2 mutations are modest at least at the level of transcription, demonstrating that additional studies are needed to clarify whether Lrrk2 affects neuroinflammation in an endogenous context.
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Project description:We used the RNA-Sequencing to obtain transcriptomic profiles of LRRK2 wild-type (WT) and knock-out (KO) microglia cells treated with α-synuclein pre-formed fibrils (PFFs) or lipopolysaccharide (LPS) as a general inflammatory insult. Conclusion: overall, the results suggest that microglial LRRK2 may contribute to the pathogenesis of PD via altered oxidative stress signaling.
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Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson’s disease (PD) while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in over-expression cell models while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in post-mortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild type mice, accompanied by striatal accumulation of ferritin. Conclusion: Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia. Neuroinflammation remodels endolysosomal gene expression in microglia, in vitro and in vivo.
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