Biomarkers of Leucine‐Rich Repeat Kinase 2 ( <scp>LRRK2)</scp> and Lysosomal Dysfunction in Progressive Supranuclear Palsy
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: levels. LRRK2 genotypes (rs76904798 and rs2242367) and 1-year change in Progressive Supranuclear Palsy Rating Scale (PSPRS) scores were obtained. RESULTS: . 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. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Authors
- Anjum Misbahuddin
- Raquel Real (ORCID: https://orcid.org/0000-0001-8117-742X)
- Marte Theilmann Jensen (ORCID: https://orcid.org/0000-0002-3727-9477)
- Riona Fumi (ORCID: https://orcid.org/0009-0007-4917-6559)
- Thomas T. Warner (ORCID: https://orcid.org/0000-0001-6195-6995)
- Danielle Graham (ORCID: https://orcid.org/0000-0003-2922-6268)
- Megan Hodgson
- David Vaughan (ORCID: https://orcid.org/0000-0001-7303-6416)
- Annelies Quaegebeur (ORCID: https://orcid.org/0000-0001-5357-9341)
- Edwin Jabbari (ORCID: https://orcid.org/0000-0001-6844-882X)
- B Ghosh
- Eleanor J. Stafford (ORCID: https://orcid.org/0000-0003-2451-4308)
- Christopher Kobylecki (ORCID: https://orcid.org/0000-0002-7797-0756)
- Zane Jaunmuktane (ORCID: https://orcid.org/0000-0001-7738-8881)
- Esther Sammler (ORCID: https://orcid.org/0000-0003-3218-7116)
- Kieren Allinson (ORCID: https://orcid.org/0000-0003-3468-2110)
- Alistair Church
- Huw R. Morris (ORCID: https://orcid.org/0000-0002-5473-3774)
- Olaf Ansorge (ORCID: https://orcid.org/0000-0003-1825-5434)
- Omar S. Mabrouk (ORCID: https://orcid.org/0000-0001-5325-1944)
- K P Bhatia
- Alan A Shomo
- Michele T.M. Hu
- Louise‐Kristine Nielsen
- Joshua L.I. Frost (ORCID: https://orcid.org/0009-0002-9729-0077)
- Lesley Wu
- P. Nigel Leigh
- James B. Rowe (ORCID: https://orcid.org/0000-0001-7216-8679)
Institutions
- Brighton and Sussex Medical School (GB)
- Biogen (United States) (US)
- Queen Mary University of London (GB)
- University of Dundee (GB)
- MRC Cognition and Brain Sciences Unit (GB)
- Manchester Academic Health Science Centre (GB)
- Royal Gwent Hospital (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- University of Oxford (GB)
- Manchester University NHS Foundation Trust (GB)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- Centre for Movement Disorders (CA)
- Queen's Hospital (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
- Medical Research Council (GB)
- KU Leuven (BE)
Publication Details
- Journal
- Movement Disorders
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1002/mds.70295
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- CurePSP
- PSP Association
- National Institute for Health and Care Research
- University of Oxford
- Medical Research Council