Fig. 6

Proteomic analysis of changes in kidney between G2019S LRRK2 MLi-2 and G2019S vehicle 10-week treated mouse cohorts. a Volcano plot showing changes in protein levels following chronic treatment, depicted as log2 fold changes (x-axis) versus the −log10 of adjusted p-values (y-axis) for each protein. A number of endolysosomal proteins were upregulated, including legumain and other lysosomal proteases in kidneys of G2019S LRRK2 KI mice that received chronic MLi-2 treatment for 10 weeks, compared to vehicle G2019S KI controls. b Heat maps of selected significant hits across the WT, G2019S KI and LRRK2 KO vehicle cohorts as well as the G2019S KI chronic MLi-2 cohort, highlighting proteins involved in vesicular trafficking, lipid metabolism, transferrin recycling and mitochondrial homeostasis. Z score is used for scaling. Using unsupervised hierarchical clustering we show that the G2019S MLi-2 and LRRK2 KO mice cluster together, suggesting that chronic LRRK2 inhibition mimics a LRRK2 KO effect in kidney. c Bubble plot showing GO:CC term enrichment in the significant total protein hits highlights enrichment for endolysosomal processes and compartments. d Volcano plot showing changes in phospho-proteins in G2019S MLi-2 treated vs G2019S untreated mice, highlighting dysregulation of proteins involved in trafficking, glucose transport and metabolism, and the TCA cycle e. f Bubble plot showing GO:CC term enrichment in the significant phospho-peptide hits highlights enrichment for endolysosomal processes as well as kidney-specific functional processes. Volcano plots key: grey = non-significant, blue = < 0.05 p-value, green = > 1.4x log fold change, red = < 0.05 p-value and > 1.4x log fold change