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Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism
Brain ( IF 10.6 ) Pub Date : 2020-10-08 , DOI: 10.1093/brain/awaa246
Max Borsche 1, 2 , Inke R König 3 , Sylvie Delcambre 4 , Simona Petrucci 5, 6 , Alexander Balck 1, 2 , Norbert Brüggemann 1, 2 , Alexander Zimprich 7 , Kobi Wasner 4 , Sandro L Pereira 4 , Micol Avenali 8 , Christian Deuschle 9, 10 , Katja Badanjak 4 , Jenny Ghelfi 4 , Thomas Gasser 9, 10 , Meike Kasten 1, 11 , Philip Rosenstiel 12 , Katja Lohmann 1 , Kathrin Brockmann 9, 10 , Enza Maria Valente 8, 13 , Richard J Youle 14 , Anne Grünewald 1, 4 , Christine Klein 1
Affiliation  

There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson’s disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson’s disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson’s disease patients. These results highlight the potential of IL6 as progression marker in Parkinson’s disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson’s disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson’s disease and Parkinson’s disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson’s disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson’s disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson’s disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson’s disease, at least in this subset of patients.

中文翻译:

线粒体损伤相关炎症凸显 PRKN/PINK1 帕金森病的生物标志物

越来越多的证据表明炎症在帕金森病中发挥作用。最近对小鼠模型的研究表明,parkin 和 PINK1 缺陷会导致线粒体自噬受损,从而导致线粒体 DNA (mtDNA) 的释放,从而引发炎症。具体而言,CGAS(环 GMP-AMP 合酶)-STING(干扰素基因刺激剂)途径可减轻先天免疫系统的激活,可量化为白细胞介素 6 (IL6) 水平的增加。然而,IL6 和循环游离细胞 mtDNA 在携带PRKN / PINK1突变的未受影响和受影响个体以及特发性帕金森病患者中的作用仍然难以捉摸。我们研究了三级运动障碍中心两组 245 名参与者血清中的 IL6、C 反应蛋白和循环游离线粒体 DNA。我们采用了假设驱动的基于排名的统计方法来调整多重测试。我们在德国队列中检测到 (i) 与健康对照受试者相比,双等位基因PRKN / PINK1突变患者的 IL6 水平升高,支持炎症在PRKN / PINK1相关帕金森病中发挥作用的概念。此外,对PRKN / PINK1双等位基因和杂合突变患者的比较表明了基因剂量效应。IL6 水平的差异在第二个独立的意大利队列中得到了验证;(ii) PRKN / PINK1突变携带者的 IL6 水平与疾病持续时间之间存在相关性,而特发性帕金森病患者则没有观察到这种相关性。这些结果强调了 IL6 作为PRKN / PINK1突变导致的帕金森病进展标志物的潜力;(iii) 与特发性帕金森病相比,双等位基因或杂合PRKN / PINK1突变患者的循环无细胞 mtDNA 血清水平升高,这与之前在小鼠模型中的发现一致。相比之下,未受影响的PRKN / PINK1突变杂合子携带者的循环游离细胞 mtDNA 浓度与对照水平相当。(iv) 循环游离 mtDNA 水平具有良好的预测潜力,可区分特发性帕金森病和与PRKN / PINK1杂合突变相关的帕金森病,为PRKNPINK1杂合突变的作用提供功能证据。作为帕金森病的危险因素。综上所述,我们的研究进一步表明,由于线粒体自噬受损和随后的 mtDNA 释放而导致的炎症与PRKN / PINK1相关的帕金森病的发病机制有关。在携带PRKN/PINK1突变的个体中,IL6 和循环游离细胞 mtDNA 水平可能分别作为帕金森病状态和进展的标志。最后,我们的研究表明,用抗炎药物靶向免疫系统有可能影响帕金森病的病程,至少在这部分患者中是这样。
更新日期:2020-10-26
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