Ex Vivo LRRK2 Activation in Asian G2385R and R1628P Variant Carriers and Idiopathic Parkinson's Disease
Ex Vivo LRRK2 Activation in Asian G2385R and R1628P Variant Carriers and Idiopathic Parkinson's Disease
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Original abstract
Abstract Background Leucine‐rich repeat kinase 2 (LRRK2) kinase inhibition is a promising therapeutic strategy for Parkinson's disease (PD), but the functional impact of Asian‐prevalent LRRK2 p.G2385R and p.R1628P variants remains unclear. Robust patient stratification and target engagement markers are needed for global LRRK2‐targeted trials. Objective The aim of this study was to characterize ex vivo LRRK2 activation status and its clinical correlates in patients with PD carrying LRRK2 p.G2385R and/or p.R1628P variants and in patients with idiopathic PD (iPD). Methods We recruited 242 participants: patients with PD carrying LRRK2 p.G2385R (PD‐G2385R; n = 57), p.R1628P (PD‐R1628P; n = 61), or both (n = 5); patients with iPD (n = 61); and healthy control subjects (HCs; n = 58). Monocyte LRRK2 activity markers (pRab10 Thr73 and pLRRK2 Ser935 ) were analyzed using multiplexed quantitative immunoblotting. Clinical severity was assessed using the International Parkinson and Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, Clinical Impression of Severity Index for PD, and Montreal Cognitive Assessment. Results Compared with HCs, pRab10 Thr73 was elevated (indicative of LRRK2 kinase hyperactivation) in PD‐G2385R (~1.2‐fold, P = 0.011) and in double‐variant carriers (~2.8‐fold, P = 0.008), but not in PD‐R1628P or iPD. Inversely correlated with pRab10 Thr73 ( r s = −0.611, P < 0.001), pLRRK2 Ser935 was reduced (indicative of a more active LRRK2 conformation) in all PD subgroups (lowest in double‐variant carriers). All double‐variant carriers, the majority of single‐variant carriers, and one‐third of participants with iPD had pRab10 Thr73 greater than the control median. Higher pRab10 Thr73 correlated with better cognition. Conclusions LRRK2 kinase activity is enhanced in patients with PD carrying LRRK2 p.G2385R, with further elevation observed in a small group of double‐variant carriers. Elevated kinase activity in a subset of iPD underscores the relevance of LRRK2 signaling and therapeutics beyond coding variants. The observed interindividual variability indicates additional genetic or environmental modifiers and highlights the need for biochemical stratification beyond genotyping in future LRRK2 trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.