Functional and Structural Characterization of LRRK2 p.V1447L in Parkinson's Disease

TY - JOUR

T1 - Functional and Structural Characterization of LRRK2 p.V1447L in Parkinson's Disease

AU - Sammler, Esther

AU - Pratuseviciute, Neringa

AU - Alessi, Dario

AU - Lis, Paweł

AU - Weber, Sacha

AU - Arnaud, Lionel

N1 - Publisher Copyright: © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PY - 2025/7/30

Y1 - 2025/7/30

N2 - Background: Gain-of-kinase-function variants in LRRK2 are a leading cause of monogenic Parkinson's disease (PD). Objectives: We tested the functional impact of a novel LRRK2 variant p.V1447L identified in a young-onset PD patient in vivo in peripheral blood, as well as in a robust cellular assay, alongside other variants in close proximity to V1447. Methods: We measured LRRK2-dependent Rab10 phosphorylation in neutrophils and monocytes of a LRRK2 p.V1447L carrier with PD. We performed structural mapping and evaluated the potential impact of other LRRK2 variants at and around LRRK2 V1447. Results: LRRK2 p.V1447L strongly increases LRRK2 kinase activity. We identified additional variants in the LRRK2 ROC:COR B interface with critical impact on kinase activity and demonstrated that different substitutions at the same residue can have opposing effects. Conclusions: We recommend reclassifying LRRK2 p.V1447L from variant of uncertain significance to likely pathogenic. Our study expands the range of putative loss-of-kinase function variants to LRRK2 missense variants.

AB - Background: Gain-of-kinase-function variants in LRRK2 are a leading cause of monogenic Parkinson's disease (PD). Objectives: We tested the functional impact of a novel LRRK2 variant p.V1447L identified in a young-onset PD patient in vivo in peripheral blood, as well as in a robust cellular assay, alongside other variants in close proximity to V1447. Methods: We measured LRRK2-dependent Rab10 phosphorylation in neutrophils and monocytes of a LRRK2 p.V1447L carrier with PD. We performed structural mapping and evaluated the potential impact of other LRRK2 variants at and around LRRK2 V1447. Results: LRRK2 p.V1447L strongly increases LRRK2 kinase activity. We identified additional variants in the LRRK2 ROC:COR B interface with critical impact on kinase activity and demonstrated that different substitutions at the same residue can have opposing effects. Conclusions: We recommend reclassifying LRRK2 p.V1447L from variant of uncertain significance to likely pathogenic. Our study expands the range of putative loss-of-kinase function variants to LRRK2 missense variants.

KW - LRRK2

KW - Parkinson's disease

KW - Rab10 phosphorylation

KW - genetics

KW - peripheral blood neutrophils

UR - https://www.scopus.com/pages/publications/105012481717

U2 - 10.1002/mds.30284

DO - 10.1002/mds.30284

M3 - Article

C2 - 40879463

SN - 0885-3185

JO - Movement Disorders

JF - Movement Disorders

ER -