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

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