Exosome LRRK2 in Predicting Parkinson Disease Phenotypes

描述（由申请人提供）：“预测帕金森病表型的外泌体LRRK2”目前迫切需要预测帕金森病（PD）易感性和进展的定量生物标志物。这些生物标记物将有助于开发减缓或停止疾病的新疗法。PD具有明确的遗传成分，有助于疾病易感性。特别是一个基因，富含亮氨酸的重复激酶2 (LRRK2)，在一些人群中普遍存在致病性错义突变。通过全基因组关联研究，LRRK2进一步与PD易感性相关。致病性LRRK2突变上调LRRK2激酶活性，并增加自磷酸化残基丝氨酸S1292 （pS1292）的水平。在我们之前的项目“PDBP探索性实验室和分析项目”（U18 NS082132）中，我们主要研究临床样品中LRRK2的分析和测量。我们发现，自磷酸化的LRRK2 （pS1292-LRRK2）可以在脑脊液（CSF）和尿液的外泌体中检测和定量。我们发现G2019S-LRRK2突变携带者的尿外泌体中pS1292-LRRK2水平升高（约5倍）。在G2019S-LRRK2突变携带者中，pS1292-LRRK2水平成功预测PD临床表现。我们进一步分析了来自阿拉巴马大学伯明翰分校帕金森病生物标志物项目（UAB PDBP）的大量病例和对照（n=160）中的pS1292-LRRK2水平，发现pS1292-LRRK2水平预测了患者的PD表型。在这里，我们将确定从尿液和脑脊液中纯化的外泌体pS1292-LRRK2在预测早期和中期特发性PD病例以及LRRK2突变携带者的PD易感性和进展方面的潜力。项目的成功将包括发现LRRK2在PD发病机制中的作用的新见解，以及开发一种新的生物标志物（外泌体pS1292-LRRK2），该标志物可能预测LRRK2突变携带者的PD表现。成功预测LRRK2突变携带者将继续发展为PD，将有助于未来LRRK2定向治疗的临床试验设计。最后，我们预测新的生物标志物外泌体pS1292- LRRK2可能有助于对特发性PD患者进行分层，这些患者将经历PD症状的快速进展，而不是那些更良性的疾病病程。识别预后不良的PD病例有助于医生进行治疗选择和设计新的神经保护疗法的临床试验。

DESCRIPTION (provided by applicant): "Exosome LRRK2 in Predicting Parkinson Disease Phenotypes" There is a critical need for quantitative biomarkers that predict Parkinson disease (PD) susceptibility and progression. Such biomarkers would aid the development of new therapies that slow or halt disease. PD has a clear genetic component that contributes to disease susceptibility. One gene in particular, leucine-rich repeat kinase 2 (LRRK2), harbors pathogenic missense mutations prevalent in some populations. LRRK2 is further linked to PD susceptibility through genome-wide association studies. Pathogenic LRRK2 mutations upregulate LRRK2 kinase activity and increase levels of the auto phosphorylated residue serine S1292 (pS1292). In our previous project "Exploratory Laboratory and Analysis Projects in PDBP" (U18 NS082132), we focused our efforts on analyzing and measuring LRRK2 in clinical samples. We discovered that auto phosphorylated LRRK2 (pS1292-LRRK2) could be detected and quantified in exosome fractions from both cerebral-spinal fluid (CSF) and urine. We found elevated levels (~5 fold) of pS1292-LRRK2 in urinary exosomes from G2019S-LRRK2 mutation carriers with PD. In G2019S-LRRK2 mutation carriers, pS1292-LRRK2 levels successfully predicting clinical PD manifestation. We further analyzed pS1292-LRRK2 in a large cohort of cases and controls (n=160) from the University of Alabama at Birmingham Parkinson's Disease Biomarker Program (UAB PDBP) and found that pS1292-LRRK2 levels predicted PD phenotypes in patients. Here we will determine the potential of exosome pS1292-LRRK2, purified from urine and CSF, in predicting PD susceptibility and progression in both early and mid-stage idiopathic PD cases as well as in LRRK2 mutation carriers. Project success will include the discovery of novel insights into the role of LRRK2 in the pathogenesis of PD and the development of a novel biomarker (exosome pS1292-LRRK2) that may predict PD manifestation in LRRK2 mutation carriers. The successful prediction of LRRK2 mutation carriers that will go on to develop PD would aid in future clinical trial design for LRRK2-directed therapies. Finally, we predict that the novel biomarker exosome pS1292- LRRK2 may help stratify idiopathic PD patients that will experience rapid progression of PD symptoms from those with more benign disease courses. Identification of PD cases with a poor prognosis would assist physicians in making treatment choices and clinical trial design for novel neuroprotective therapies.