Changes in matrix metalloprotease activity and progranulin levels may contribute to the pathophysiological function of mutant leucine-rich repeat kinase 2
Changes in matrix metalloprotease activity and progranulin levels may contribute to the pathophysiological function of mutant leucine-rich repeat kinase 2
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DOI：
10.1002/glia.22663
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发表时间：
2014-07-01
期刊：
影响因子：
6.2
通讯作者：
Gillardon, Frank
中科院分区：
文献类型：
--
作者：
Caesar, Mareike;Felk, Sandra;Gillardon, Frank
越来越多的证据表明，帕金森病（PD）相关的富含亮氨酸重复序列激酶2（LRRK 2）在外周和脑内免疫细胞中发挥作用。此外，在几种慢性神经退行性疾病中已经证明了抗炎神经营养蛋白颗粒蛋白前体（PGRN）的失调。在这里，我们表明，PGRN水平显着降低LRRK 2（R1441 G）突变小鼠成纤维细胞，白细胞和小胶质细胞的条件培养基，而促炎因子，如白细胞介素-1 β和角质形成细胞衍生的趋化因子的水平显着增加。在从症状前LRRK 2（G2019 S）突变携带者分离的培养的人成纤维细胞的上清液中也检测到降低的PGRN水平，而线粒体功能不受影响。此外，在LRRK 2（R1441 G）突变型小胶质细胞中，基质金属蛋白酶（MMP）2的中等水平增加，而MMP 9减少。来自LRRK 2（R1441 G）突变小鼠脑的突触神经小体中MMP底物ICAM-5和α-突触核蛋白的蛋白水解裂解增加表明净突触MMP活性增加。在症状前LRRK 2突变小鼠的脑脊液中PGRN水平降低，而在老年症状突变小鼠中PGRN水平升高。值得注意的是，携带LRRK 2突变的PD患者的脑脊液中PGRN水平也增加，但在特发性PD患者和健康对照供体中则没有。我们的数据表明，外周和脑驻留免疫细胞的促炎活性可能特别有助于LRRK 2突变引起的帕金森病的早期阶段。GLIA 2014;62：1075-1092
Increasing evidence suggests that Parkinson's disease (PD)-linked Leucine-rich repeat kinase 2 (LRRK2) has a role in peripheral and brain-resident immune cells. Furthermore, dysregulation of the anti-inflammatory, neurotrophic protein progranulin (PGRN) has been demonstrated in several chronic neurodegenerative diseases. Here we show that PGRN levels are significantly reduced in conditioned medium of LRRK2(R1441G) mutant mouse fibroblasts, leukocytes, and microglia, whereas levels of proinflammatory factors, like interleukin-1 beta and keratinocyte-derived chemokine, were significantly increased. Decreased PGRN levels were also detected in supernatants of cultured human fibroblasts isolated from presymptomatic LRRK2(G2019S) mutation carriers, while mitochondrial function was unaffected. Furthermore, medium levels of matrix metalloprotease (MMP) 2 increased, whereas MMP 9 decreased in LRRK2(R1441G) mutant microglia. Increased proteolytic cleavage of the MMP substrates ICAM-5 and alpha-synuclein in synaptoneurosomes from LRRK2(R1441G) mutant mouse brain indicates increased net synaptic MMP activity. PGRN levels were decreased in the cerebrospinal fluid of presymptomatic LRRK2 mutant mice, whereas PGRN levels were increased in aged symptomatic mutant mice. Notably, PGRN levels were also increased in the cerebrospinal fluid of PD patients carrying LRRK2 mutations, but not in idiopathic PD patients and in healthy control donors. Our data suggest that proinflammatory activity of peripheral and brain-resident immune cells may particularly contribute to the early stages of Parkinson's disease caused by LRRK2 mutations. GLIA 2014;62:1075-1092