■富含亮氨酸的重复激酶2基因的突变在帕金森病的散发性和家族性病例中高度相关。特定疗法正在进入临床试验,但患者分层仍然具有挑战性。微RNA表达水平失调已被提议作为散发性帕金森病的生物标志物候选物。
■在这项概念验证研究中,我们评估了细胞外miRNA特征识别帕金森病中LRRK2驱动的分子模式的潜力。
■我们通过RT-qPCR在10名散发性帕金森病患者中测量了91个miRNAs的表达水平,使用血浆和脑脊液的10个LRRK2突变携带者和11个健康对照。我们使用热图和t检验比较了miRNA特征。接下来,我们应用了分组排序算法,并测试了分组预测的敏感性和特异性.
■miR-29c-3p在LRRK2突变携带者和散发性病例之间差异表达,miR-425-5p具有显著性。个体在主成分分析中沿着突变状态聚集。预测模型中的群体隶属度预测精度高(灵敏度高达89%,特异性高达70%)。miRs-128-3p,29c-3p,223-3p,在所有分析中,424-5p被确定为有希望的鉴别器。
■LRRK2突变状态影响血浆中测量的细胞外miRNA特征,并将突变携带者与散发性帕金森病患者分开。监测LRRK2miRNA特征可能是测试LRRK2靶向疗法的药物功效的有趣方法。鉴于样本量小,建议的方法需要在更大的队列中进行验证.
我们知道,一种叫做亮氨酸丰富重复激酶2的基因的改变在遗传性和非遗传性帕金森病病例中都很重要。我们还知道,目前正在开发专门针对LRRK2的帕金森病治疗方法。开发这种治疗方法的挑战,然而,是如何准确地识别患者谁可以从这些疗法中受益,并观察治疗是否在分子水平上与其目标相互作用。在这项研究中,我们测试了LRRK2基因改变的个体是否显示出独特的小RNA分子模式,称为microRNAs。我们测量了LRRK2基因发生改变的个体血液中存在的91个microRNA的量,并将其模式与患有非遗传性帕金森病的患者和健康对照进行了比较。我们发现称为miR-29c-3p的特定microRNA的量在有或没有LRRK2基因改变的个体之间是不同的。此外,我们开发了可以根据血浆中的microRNA模式预测某人是否具有LRRK2突变的模型.当然,我们有更简单的方法来找到这些基因改变,但是我们的研究结果表明,LRRK2的变化导致血液中microRNA模式的改变。这可以帮助我们观察试图逆转这些变化的LRRK2特异性治疗的效果。正如我们所知,LRRK2在一些非遗传性帕金森病患者中也起作用,这种microRNA模式甚至可以帮助我们识别这些个体。值得注意的是,我们的研究涉及少数人,因此,需要对更大的群体进行进一步的研究来证实我们的发现。
UNASSIGNED: Mutations in the Leucine Rich Repeat Kinase 2 gene are highly relevant in both sporadic and familial cases of Parkinson\'s disease. Specific therapies are entering clinical trials but patient stratification remains challenging. Dysregulated microRNA expression levels have been proposed as biomarker candidates in sporadic Parkinson\'s disease.
UNASSIGNED: In this proof-of concept study we evaluate the potential of extracellular miRNA signatures to identify
LRRK2-driven molecular patterns in Parkinson\'s disease.
UNASSIGNED: We measured expression levels of 91 miRNAs via RT-qPCR in ten individuals with sporadic Parkinson\'s disease, ten
LRRK2 mutation carriers and eleven healthy controls using both plasma and cerebrospinal fluid. We compared miRNA signatures using heatmaps and t-tests. Next, we applied group sorting algorithms and tested sensitivity and specificity of their group predictions.
UNASSIGNED: miR-29c-3p was differentially expressed between LRRK2 mutation carriers and sporadic cases, with miR-425-5p trending towards significance. Individuals clustered in principal component analysis along mutation status. Group affiliation was predicted with high accuracy in the prediction models (sensitivity up to 89%, specificity up to 70%). miRs-128-3p, 29c-3p, 223-3p, and 424-5p were identified as promising discriminators among all analyses.
UNASSIGNED: LRRK2 mutation status impacts the extracellular miRNA signature measured in plasma and separates mutation carriers from sporadic Parkinson\'s disease patients. Monitoring
LRRK2 miRNA signatures could be an interesting approach to test drug efficacy of
LRRK2-targeting therapies. In light of small sample size, the suggested approach needs to be validated in larger cohorts.
We know that alterations in a gene called Leucine Rich Repeat Kinase 2 are important in both inherited and non-inherited cases of Parkinson’s disease. We also know that treatments for Parkinson’s disease specifically targeting
LRRK2 are currently being developed. Challenges for developing such a treatment, however, are how to accurately identify patients who could benefit from these therapies and to observe whether the treatment interacts with its target on a molecular level. In this study, we tested whether individuals with an alteration in the
LRRK2 gene display a distinct pattern of small RNA molecules, called microRNAs. We measured the amount of 91 microRNAs present in blood of individuals with an alteration in the LRRK2 gene and compared their pattern to patients with a non-inherited form of Parkinson’s disease and healthy controls.We found that the amount of a specific microRNA called miR-29c-3p was different between individuals with or without an alteration of the LRRK2 gene. Additionally, we developed models that could predict whether someone had a LRRK2 mutation based on the microRNA pattern in the plasma. Of course, we have easier methods to find these gene alterations, but our findings suggest that changes of LRRK2 result in a shift of microRNA patterns in the blood. This could help us to observe the effects of a LRRK2 specific treatment which tries to revert these changes. As we know that LRRK2 also plays a role in some patients with a non-inherited form of Parkinson’s disease, this microRNA pattern could maybe even help us to identify these individuals. It is important to note that our study involved a small number of individuals, so that further research with larger groups is needed to confirm our findings.