Brain and Mind Centre, Central Clinical School, University of Sydney, Camperdown, NSW, Australia.
Forefront Parkinson's Disease Research Clinic, Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
Mov Disord. 2019 Mar;34(3):406-415. doi: 10.1002/mds.27601. Epub 2018 Dec 30.
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.
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.
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.
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.
富含亮氨酸重复激酶 2 是治疗帕金森病的潜在治疗靶点，富含亮氨酸重复激酶 2 抑制剂的临床试验正在进行中。本研究的目的是评估新的富含亮氨酸重复激酶 2 底物 Rab10 的磷酸化，以潜在地作为富含亮氨酸重复激酶 2 抑制剂临床试验的目标结合生物标志物和/或患者富集生物标志物。
从帕金森病患者和匹配的对照中分离外周血单核细胞和中性粒细胞，并在体外用富含亮氨酸重复激酶 2 抑制剂处理。免疫印迹法用于测量富含亮氨酸重复激酶 2 和 Rab10 及其磷酸化水平。通过多重酶联免疫吸附试验测量血浆炎性细胞因子。
对照和帕金森病患者的单核细胞和中性粒细胞对富含亮氨酸重复激酶 2 抑制剂的治疗反应相同。对照和帕金森病患者的单核细胞中富含亮氨酸重复激酶 2 水平相同，而帕金森病中性粒细胞中富含亮氨酸重复激酶 2 水平显著增加。对照和帕金森病患者的 Rab10 T73 磷酸化水平相似，与富含亮氨酸重复激酶 2 水平无关。免疫细胞中富含亮氨酸重复激酶 2 和 Rab10 T73 磷酸化水平与血浆炎性细胞因子水平相关。
Rab10 T73 磷酸化似乎是富含亮氨酸重复激酶 2 抑制剂临床试验中潜在的目标结合生物标志物。然而，富含亮氨酸重复激酶 2 和 Rab10 磷酸化之间缺乏关联，使得 Rab10 磷酸化作为患者富集生物标志物的潜在用途变得复杂。尽管需要复制，但帕金森病患者中性粒细胞中富含亮氨酸重复激酶 2 水平的增加可能具有患者分层的潜力。外周免疫细胞中的富含亮氨酸重复激酶 2 活性可能有助于炎症表型。国际帕金森病和运动障碍学会 2018 年。
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