LRRK2 levels in immune cells are increased in Parkinson's disease.
LRRK2 levels in immune cells are increased in Parkinson's disease.
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DOI：
10.1038/s41531-017-0010-8
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Tansey MG
中科院分区：
文献类型：
--
作者：
Cook DA;Kannarkat GT;Cintron AF;Butkovich LM;Fraser KB;Chang J;Grigoryan N;Factor SA;West AB;Boss JM;Tansey MG
与富亮氨酸重复激酶2相关的突变是帕金森病最常见的已知原因。已知富亮氨酸重复激酶2在免疫细胞中的表达及其对活化T细胞核因子的负调控功能，暗示富亮氨酸重复激酶2参与帕金森病炎症环境特征的发展。本研究的目的是确定富亮氨酸重复激酶2在免疫细胞亚群中的表达模式，并将其与帕金森病和健康受试者细胞的免疫表型相关联。采用流式细胞术对40名帕金森病患者和32名年龄和环境匹配的健康对照者的血细胞进行免疫表型分析。多重免疫分析法用于测量受刺激细胞的细胞因子输出。与健康对照组相比，帕金森病患者B细胞（p = 0.0095）、T细胞（p = 0.029）和CD16+单核细胞（p = 0.01）中富亮氨酸重复激酶2的表达增加。与健康对照相比，帕金森病患者单核细胞和分裂T细胞中富含亮氨酸的重复激酶2的诱导也有所增加。此外，与健康对照相比，帕金森病患者单核细胞分泌更多的炎性细胞因子，帕金森病患者T细胞中细胞因子的表达与富含亮氨酸的重复激酶2的表达呈正相关，而健康对照则没有。最后，与T细胞HC相比，帕金森病中限制T细胞激活信号的调节表面蛋白CTLA-4（细胞毒性T淋巴细胞相关蛋白4）减少（p = 0.029）。综上所述，这些发现提示富亮氨酸重复激酶2在免疫细胞和帕金森病中具有调节作用。功能上，富亮氨酸重复激酶2在t细胞亚群中的表达水平、细胞因子的表达和分泌以及t细胞激活状态之间的正相关表明，针对富亮氨酸重复激酶2进行治疗干预可能对免疫细胞功能有直接影响。免疫细胞中高水平的富亮氨酸重复激酶2 （LRRK2）破坏帕金森病（PD）患者的免疫系统功能。LRRK2突变是帕金森病最常见的遗传原因。尽管在许多免疫细胞中发现了LRRK2，但研究工作主要集中在确定其对神经元功能的影响上。美国埃默里大学的Malu G. Tansey及其同事比较了40名迟发性PD患者和32名年龄和环境匹配的健康对照者免疫细胞中LRKK2的水平和功能。与对照细胞相比，PD患者的细胞具有更高水平的LRKK2蛋白，并在刺激反应中产生更多的促炎分子。由于已知炎症反应加剧会加重神经退行性变，监测LRKK2水平可能有助于评估遗传性和散发性PD病例的疾病进展。
Mutations associated with leucine-rich repeat kinase 2 are the most common known cause of Parkinson’s disease. The known expression of leucine-rich repeat kinase 2 in immune cells and its negative regulatory function of nuclear factor of activated T cells implicates leucine-rich repeat kinase 2 in the development of the inflammatory environment characteristic of Parkinson’s disease. The aim of this study was to determine the expression pattern of leucine-rich repeat kinase 2 in immune cell subsets and correlate it with the immunophenotype of cells from Parkinson’s disease and healthy subjects. For immunophenotyping, blood cells from 40 Parkinson’s disease patients and 32 age and environment matched-healthy control subjects were analyzed by flow cytometry. Multiplexed immunoassays were used to measure cytokine output of stimulated cells. Leucine-rich repeat kinase 2 expression was increased in B cells (p = 0.0095), T cells (p = 0.029), and CD16+ monocytes (p = 0.01) of Parkinson’s disease patients compared to healthy controls. Leucine-rich repeat kinase 2 induction was also increased in monocytes and dividing T cells in Parkinson’s disease patients compared to healthy controls. In addition, Parkinson’s disease patient monocytes secreted more inflammatory cytokines compared to healthy control, and cytokine expression positively correlated with leucine-rich repeat kinase 2 expression in T cells from Parkinson’s disease but not healthy controls. Finally, the regulatory surface protein that limits T-cell activation signals, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), was decreased in Parkinson’s disease compared to HC in T cells (p = 0.029). In sum, these findings suggest that leucine-rich repeat kinase 2 has a regulatory role in immune cells and Parkinson’s disease. Functionally, the positive correlations between leucine-rich repeat kinase 2 expression levels in T-cell subsets, cytokine expression and secretion, and T-cell activation states suggest that targeting leucine-rich repeat kinase 2 with therapeutic interventions could have direct effects on immune cell function. High levels of leucine-rich repeat kinase 2 (LRRK2) in immune cells disrupt immune system function in patients with Parkinson’s disease (PD). Mutations in LRRK2 are the most common genetic cause of PD. Although LRRK2 is found in many immune cells, research efforts have focussed on determining its effects on neuronal function. Malu G. Tansey at Emory University, USA, and colleagues compared the levels and function of LRKK2 in immune cells from 40 late-onset PD patients and 32 age- and environment-matched healthy controls. The cells from PD patients had higher levels of LRKK2 protein and produced more pro-inflammatory molecules in response to stimulation than the control cells. As exacerbated inflammatory responses are known to aggravate neurodegeneration, monitoring LRKK2 levels may aid the assessment of disease progression in both inherited and sporadic cases of PD.