BioProject

BACKGROUND: Previous data implicates neuroinflammation in the pathogenesis of Parkinson’s disease (PD). More...

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. Overall design: We injected WT, Lrrk2 G2019S, and Lrrk2 R1441C knockin mice intrastriatally with PBS or LPS, and extracted the striatum and midbrain for scRNA-seq processing. Less...