LRRK2‐mediated Rab10 phosphorylation in immune cells from Parkinson's disease patients

Abstract

Background: Leucine‐rich repeat kinase 2 is a potential therapeutic target for the treatment of Parkinson's disease, and clinical trials of leucine‐rich repeat kinase 2 inhibitors are in development. The objective of this study was to evaluate phosphorylation of a new leucine‐rich repeat kinase 2 substrate, Rab10, for potential use as a target engagement biomarker and/or patient enrichment biomarker for leucine‐rich repeat kinase 2 inhibitor clinical trials. Methods: Peripheral blood mononuclear cells and neutrophils were isolated from Parkinson's disease patients and matched controls, and treated ex vivo with a leucine‐rich repeat kinase 2 inhibitor. Immunoblotting was used to measure levels of leucine‐rich repeat kinase 2 and Rab10 and their phosphorylation. Plasma inflammatory cytokines were measured by multiplex enzyme‐linked immunosorbent assay. Results: Mononuclear cells and neutrophils of both controls and Parkinson's disease patients responded the same to leucine‐rich repeat kinase 2 inhibitor treatment. Leucine‐rich repeat kinase 2 levels in mononuclear cells were the same in controls and Parkinson's disease patients, whereas leucine‐rich repeat kinase 2 was significantly increased in Parkinson's disease neutrophils. Rab10 T73 phosphorylation levels were similar in controls and Parkinson's disease patients and did not correlate with leucine‐rich repeat kinase 2 levels. Immune‐cell levels of leucine‐rich repeat kinase 2 and Rab10 T73 phosphorylation were associated with plasma inflammatory cytokine levels. Conclusions: Rab10 T73 phosphorylation appears to be a valid target engagement biomarker for potential use in leucine‐rich repeat kinase 2 inhibitor clinical trials. However, a lack of association between leucine‐rich repeat kinase 2 and Rab10 phosphorylation complicates the potential use of Rab10 phosphorylation as a patient enrichment biomarker. Although replication is required, increased leucine‐rich repeat kinase 2 levels in neutrophils from Parkinson's disease patients may have the potential for patient stratification. leucine‐rich repeat kinase 2 activity in peripheral immune cells may contribute to an inflammatory phenotype. © 2018 International Parkinson and Movement Disorder Society