Biomarkers of LRRK2 and lysosomal dysfunction in Progressive Supranuclear Palsy

BackgroundCommon and rare genetic variants in LRRK2 have been linked with sporadic and familial Parkinsons disease (PD). Recently, we discovered that common genetic variation near the LRRK2 locus determined survival in progressive supranuclear palsy (PSP). Our study aimed to explore biomarkers of LRRK2 and lysosomal dysfunction in PSP. MethodsImmunoblotting was used to measure total LRRK2 and LRRK2-dependent Rab10 phosphorylation at Threonine73 (pRab10Thr73) in neutrophil and monocyte samples from PSP and control participants. Urine samples were applied to a multiplexed assay to quantitate bis(monoacylglycerol)phosphate (BMP) species as markers of lysosomal dysfunction. CSF samples from a wider cohort of PSP and control participants were applied to a stable isotope standards and capture by anti-peptide antibodies assay to measure total LRRK2 and pRab10Thr73 levels. LRRK2 genotypes (rs76904798 and rs2242367) and 1-year change in PSP rating scale scores were obtained. Results61 PSP and 34 control participants were included. Total urine 22:6-BMP levels were higher in PSP vs. control samples (p=0.04) and correlated with CSF total LRRK2 levels (r=0.49, p=0.04). In PSP, carriers of the alternate allele (CT and TT genotypes) at the LRRK2 PD risk variant, rs76904798, had higher levels of CSF total LRRK2 vs. CC genotype (p=0.02). A similar but non-significant trend was observed for the LRRK2 PSP survival variant, rs2242367 (p=0.08). Baseline monocyte total LRRK2 levels predicted 1-year change in the PSP rating scale score (p=0.008). ConclusionsBiochemically defined lysosomal dysfunction is evident in PSP. Genetic and biochemical stratification may identify PSP patients that would benefit from LRRK2-targetting therapies.