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

被引：70

作者：

Atashrazm, Farzaneh ^{[1
]}

Hammond, Deborah ^{[2
]}

Perera, Gayathri ^{[1
]}

Bolliger, Marc F. ^{[3
]}

Matar, Elie ^{[1
,2
]}

Halliday, Glenda M. ^{[1
,4
,5
]}

Schule, Birgitt ^{[3
]}

Lewis, Simon J. G. ^{[1
,2
]}

Nichols, R. Jeremy ^{[3
]}

Dzamko, Nicolas ^{[1
,4
,5
]}

机构：

[1] Univ Sydney, Cent Clin Sch, Brain & Mind Ctr, Camperdown, NSW 2050, Australia

[2] Univ Sydney, Brain & Mind Ctr, Forefront Parkinsons Dis Res Clin, Camperdown, NSW, Australia

[3] Parkinsons Inst & Clin Ctr, Sunnyvale, CA USA

[4] Neurosci Res Australia, Randwick, NSW, Australia

[5] Univ NSW, Sch Med Sci, Kensington, NSW, Australia

来源：

MOVEMENT DISORDERS | 2019年 / 34卷 / 03期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

biomarker; blood; inflammation; Parkinson's disease; Rab GTPase; LRRK2; KINASE; 14-3-3; BINDING; INFLAMMATION; INHIBITORS; MUTATIONS;

D O I：

10.1002/mds.27601

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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. (c) 2018 International Parkinson and Movement Disorder Society

引用

页码：406 / 415

页数：10

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