A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

Yahaira Naaldijk, Belén Fernández, Rachel Fasiczka, Elena Fdez, Coline Leghay, Ioana Croitoru, John B. Kwok, Yanisse Boulesnane, Amelie Vizeneux, Eugenie Mutez, Camille Calvez, Alain Destée, Jean Marc Taymans, Ana Vinagre Aragon, Alberto Bergareche Yarza, Shalini Padmanabhan, Mario Delgado, Roy N. Alcalay, Zac Chatterton, Nicolas DzamkoGlenda Halliday, Javier Ruiz-Martínez, Marie Christine Chartier-Harlin, Sabine Hilfiker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they accumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate idiopathic PD patients who will benefit from LRRK2-related therapeutics.

Original languageEnglish
Article number12
Journalnpj Parkinson's Disease
Volume10
Issue number1
DOIs
StatePublished - Dec 2024
Externally publishedYes

Funding

FundersFunder number
Michael J. Fox Foundation for Parkinson's ResearchMJFF-019358, MJFF-020338

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