Beyond known mutations: Functional evidence for LRRK2 pathway activation in a subset of Parkinson’s disease patients

Background Pathogenic LRRK2 variants cause Parkinson’s disease (PD) through increased kinase activity, with VPS35 p.D620N and other rare LRRK2 variants showing similar effects. Findings in idiopathic PD suggest broader LRRK2 pathway involvement. As LRRK2-targeted therapies advance, identifying patients with elevated pathway activity beyond known mutations is essential. Methods LRRK2-dependent pRab10 ^Thr73 phosphorylation was quantified in blood neutrophils from 181 genetically enriched PD patients and 71 controls. Whole-exome sequencing identified pathogenic and rare variants. For a subset of PD patients with LRRK2 hyperactivation, an siRNA knock-down screen targeting genes carrying rare variants was performed in A549 cells. Results VPS35 p.D620N carriers showed marked hyperactivation, defining a reference threshold. Fourteen percent of PD patients without known pathogenic variants showed similar or higher activation. Knock-down studies implicated genes including NECAP2 , EIF5A2 , and TECPR1 in modulating LRRK2 signaling. Conclusions A subset of PD patients without known mutations exhibits LRRK2 hyperactivation, supporting a broader “LRRK2-driven” mechanism and the need for scalable biomarkers.