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Updated: Sep 9, 2025
Assaying the Kinase Activity of LRRK2 in vitro
Published on: January 18, 2012
Functional and Structural Characterization of LRRK2 p.V1447L in Parkinson's Disease
Neringa Pratuseviciute1, Pawel Lis1, Sacha Weber2
1Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
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:CORB 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. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Insights
A novel LRRK2 variant, p.V1447L, significantly elevates kinase activity, suggesting it is likely pathogenic in Parkinson's disease (PD). This finding expands understanding of LRRK2's role in PD pathogenesis.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Biochemistry
Background:
- Gain-of-kinase-function variants in Leucine-Rich Repeat Kinase 2 (LRRK2) are a primary genetic cause of monogenic Parkinson's disease (PD).
- Identifying the functional impact of novel LRRK2 variants is crucial for understanding PD pathogenesis.
Purpose of the Study:
- To assess the functional consequences of the LRRK2 p.V1447L variant in a patient with young-onset PD.
- To investigate the impact of other LRRK2 variants near residue 1447 on kinase activity.
Main Methods:
- Measured LRRK2-dependent Rab10 phosphorylation in immune cells (neutrophils and monocytes) from a LRRK2 p.V1447L carrier.
- Performed structural mapping of the LRRK2 protein.
- Evaluated the functional effects of variants at and around the V1447 residue.
Main Results:
- The LRRK2 p.V1447L variant markedly increases LRRK2 kinase activity.
- Additional variants at the LRRK2 ROC:CORB interface were identified, significantly affecting kinase activity.
- Substitutions at the same residue demonstrated opposing effects on kinase function.
Conclusions:
- The LRRK2 p.V1447L variant should be reclassified from 'variant of uncertain significance' to 'likely pathogenic'.
- This research broadens the spectrum of LRRK2 missense variants associated with PD, including those potentially leading to loss-of-kinase function.
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