Figure 9.

Changes in gene expression are observed in PD-implicated DA neuron subtypes in Lrrk2^G2019S mice. A) GO results comparing Sox6 cluster family across conditions. Several pathways are highly relevant to locomotor behavior and previously described dysfunction (such as synaptic organization pathways) in Lrrk2^G2019S mutant mice. B) GSEA results comparing Sox6 cluster family across conditions. While twenty pathways were positively enriched in mutant Sox6 family clusters (BH-corrected p-values < 0.05), several additional pathways were enriched in either direction using a less conservative cutoff of p < 0.1. The top five positively and negatively enriched pathways with this less conservative cutoff are shown. Pathway enrichment was similar to global changes, but more pronounced in the Sox6 family of clusters. C) GO results comparing the Sox6^Tafa1 cluster, which showed the highest expression of Anxa1, across conditions. This population has previously been shown to selectively signal during motor acceleration and shows enrichment for motor pathways as a function of Lrrk2 genotype, which could suggest DA signaling deficits in acceleration-correlated circuits and a potential substrate for subsequent motor deficits in Lrrk2^G2019S DA neurons. D) Results of SynGO analyses for Sox6 family, Calb1 family, or Sox6^Tafa1 clusters. SynGO-annotated (i.e. synaptic) genes were enriched among DEGs for ventral SNc populations, particularly Sox6^Tafa1. Of note, among these synaptic genes, Sox6^Tafa1 cluster showed much heavier enrichment for those localized to the presynapse, which may suggest subtype-specific presynaptic function in acceleration-corrected subtypes. G) Feature plot of each cell’s association with PD risk loci proposed by GWAS as calculated by scDRS scores. Clear differences are observed across clusters. H) Mean and 95% confidence intervals for PD GWAS risk (scDRS scores) for each cluster. Sox6 family of clusters are particularly elevated. I) Average risk scores with 95% confidence intervals among cluster families, as well as clusters Sox6^Tafa1 and Sox6^Vcan, the two Anxa1-expressing SNc clusters, which showed the highest average risk scores.