Biomarkers of Leucine-Rich Repeat Kinase 2 (LRRK2) and Lysosomal Dysfunction in Progressive Supranuclear Palsy

TY - JOUR

T1 - Biomarkers of Leucine-Rich Repeat Kinase 2 (LRRK2) and Lysosomal Dysfunction in Progressive Supranuclear Palsy

AU - Nielsen, Louise Kristine

AU - Frost, Joshua L.I.

AU - Vaughan, David P.

AU - Real, Raquel

AU - Fumi, Riona

AU - Jensen, Marte Theilmann

AU - Hodgson, Megan

AU - Stafford, Eleanor J.

AU - Wu, Lesley

AU - Ansorge, Olaf

AU - Quaegebeur, Annelies

AU - Allinson, Kieren S.J.

AU - Warner, Thomas T.

AU - Jaunmuktane, Zane

AU - Misbahuddin, Anjum

AU - Leigh, P. Nigel

AU - Ghosh, Boyd C.P.

AU - Bhatia, Kailash P.

AU - Church, Alistair

AU - Kobylecki, Christopher

AU - Hu, Michele T.M.

AU - Rowe, James B.

AU - Shomo, Alan A.

AU - Graham, Danielle L.

AU - Mabrouk, Omar S.

AU - Morris, Huw R.

AU - Sammler, Esther M.

AU - Jabbari, Edwin

N1 - Publisher Copyright: © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PY - 2026/7

Y1 - 2026/7

N2 - Background: Common and rare genetic variants in leucine-rich repeat kinase 2 (LRRK2) have been linked with sporadic and familial Parkinson's 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. Methods: Immunoblotting was used to measure total LRRK2 and LRRK2-dependent Rab10 phosphorylation at the threonine 73 residue (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. Cerebrospinal fluid (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 Progressive Supranuclear Palsy Rating Scale (PSPRS) scores were obtained. Results: A total of 61 PSP and 34 control participants were included. Total urine 22:6-BMP levels were higher in PSP versus control samples (P = 0.04) and correlated with CSF total LRRK2 levels (r = 0.49, P = 0.04). There were no group-level differences in monocyte and CSF levels of total LRRK2 and pRab10Thr73. 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 versus CC genotype (P = 0.02). Baseline monocyte total LRRK2 levels predicted 1-year change in the PSPRS score (P = 0.008). Conclusions: Biochemically defined lysosomal dysfunction is evident in PSP. Genetic and biochemical stratification may identify PSP patients that would benefit from LRRK2-targeting therapies.

AB - Background: Common and rare genetic variants in leucine-rich repeat kinase 2 (LRRK2) have been linked with sporadic and familial Parkinson's 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. Methods: Immunoblotting was used to measure total LRRK2 and LRRK2-dependent Rab10 phosphorylation at the threonine 73 residue (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. Cerebrospinal fluid (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 Progressive Supranuclear Palsy Rating Scale (PSPRS) scores were obtained. Results: A total of 61 PSP and 34 control participants were included. Total urine 22:6-BMP levels were higher in PSP versus control samples (P = 0.04) and correlated with CSF total LRRK2 levels (r = 0.49, P = 0.04). There were no group-level differences in monocyte and CSF levels of total LRRK2 and pRab10Thr73. 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 versus CC genotype (P = 0.02). Baseline monocyte total LRRK2 levels predicted 1-year change in the PSPRS score (P = 0.008). Conclusions: Biochemically defined lysosomal dysfunction is evident in PSP. Genetic and biochemical stratification may identify PSP patients that would benefit from LRRK2-targeting therapies.

UR - https://www.scopus.com/pages/publications/105035847417

U2 - 10.1002/mds.70295

DO - 10.1002/mds.70295

M3 - Article

C2 - 41987507

AN - SCOPUS:105035847417

SN - 0885-3185

VL - 41

SP - 1740

EP - 1749

JO - Movement Disorders

JF - Movement Disorders

IS - 7

ER -