Format

Send to

Choose Destination
Mov Disord. 2019 Mar;34(3):406-415. doi: 10.1002/mds.27601. Epub 2018 Dec 30.

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

Author information

1
Brain and Mind Centre, Central Clinical School, University of Sydney, Camperdown, NSW, Australia.
2
Forefront Parkinson's Disease Research Clinic, Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
3
Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.
4
Neuroscience Research Australia, Randwick, NSW, Australia.
5
School of Medical Sciences, University of NSW, Kensington, NSW, Australia.

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.

KEYWORDS:

Parkinson's disease; Rab GTPase; biomarker; blood; inflammation

PMID:
30597610
DOI:
10.1002/mds.27601

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center