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

Background Gain-of-kinase-function variants in LRRK2 are a leading cause for Parkinson’s disease (PD).

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 in addition to other variants in close proximity to V1447.

We measured LRRK2-dependent Rab10 phosphorylation in neutrophils and monocytes of a LRRK2 p.V1447L carrier with PD. We deployed structural modelling and evaluated the impact of additional LRRK2 variants at and around LRRK2 V1447.

LRRK2 p.V1447L strongly activates LRRK2 kinase activity. We identified additional variants in the LRRK2 ROC:CORB interface with critical impact on kinase activity and show that different substitutions at the same residue can have opposing effects.

We recommend reclassifying LRRK2 p.V1447L from VUS to likely pathogenic. Our study expands the range of putative Loss-of-kinase function variants to LRRK2 missense variants. Competing Interest Statement The authors have declared no competing interest. Funding Statement ES was supported by a CSO Senior Clinical Academic Fellowship (SCAF/18/01) and NP by a Carnegie Trust PhD studentship (PHD010656). Grant funding from the Medical Research Council MC_UU_00038/1 (Dario Alessi PL). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study participants have provided written informed consent, and ethical approval was granted by the ethics committee of the University Hospital Centre of Caen, France. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability Data that support the findings of this study are available from the corresponding author, upon reasonable request.