Exosome LRRK2 in Predicting Parkinson Disease Phenotypes

外泌体 LRRK2 预测帕金森病表型

• 批准号: 9135110
• 负责人: Andrew B West
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135110
• 关键词: Alabama; Ashkenazim; Benign; Biochemical Markers; Biological Assay; Biological Markers; Biopsy; Brain; Cerebrospinal Fluid; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Collection; Data; Dementia; Derivation procedure; Development; Diagnostic; Disease; Disease Progression; Disease susceptibility; Encapsulated; Evaluation; Future; Genes; Genetic; Genetic study; Goals; Health; Idiopathic Parkinson Disease; Impaired cognition; Individual; LRRK2 gene; Laboratories; Levodopa; Link; Liquid substance; Longitudinal Studies; Measurement; Measures; Missense Mutation; Mutation; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphotransferases; Physicians; Plasma; Population; Prognostic Marker; Proteins; Risk; Role; Sampling; Series; Serine; Severities; Severity of illness; Staging; Symptoms; Time; Tissues; Universities; Urine; Work; biobank; case control; cohort; disease phenotype; exosome; experience; genome wide association study; insight; link protein; microvesicles; motor symptom; mutation carrier; neuroprotection; novel; novel marker; novel therapeutics; outcome forecast; prognostic; programs; statistics; success; symptom treatment; treatment choice; urinary

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.

描述(由申请人提供)：“Exosome LRRK2在预测帕金森病表型中的作用”对于预测帕金森病(PD)易感性和进展的定量生物标记物的需求十分迫切。这样的生物标记物将有助于开发延缓或阻止疾病的新疗法。帕金森病具有明确的遗传成分，有助于疾病易感性。一个基因，特别是富含亮氨酸的重复蛋白激酶2(LRRK2)，含有致病错义突变，在一些人群中普遍存在。通过全基因组相关性研究，LRRK2进一步与帕金森病的易感性有关。致病的LRRK2突变上调了LRRK2的活性，增加了自身磷酸化残基丝氨酸S1292的水平(PS1292)。在我们之前的项目“PDBP中的探索性实验室和分析项目”(U18 NS082132)中，我们致力于分析和测量临床样本中的LRRK2。我们发现在脑脊液和尿液中都能检测到自身磷酸化的LRRK2(pS1292-LRRK2)。我们发现在伴有PD的G2019S-LRRK2突变携带者的尿外切体中pS1292-LRRK2水平升高(~5倍)。在G2019S-LRRK2突变携带者中，pS1292-LRRK2水平成功预测了帕金森病的临床表现。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记物计划(UAB PDBP)的大量病例和对照(n=160)中的pS1292-LRRK2，发现pS1292-LRRK2水平预测患者的PD表型。在这里，我们将确定从尿液和脑脊液中提纯的外切体pS1292-LRRK2在预测早、中期特发性帕金森病患者以及LRRK2突变携带者的帕金森病易感性和进展方面的潜力。项目的成功将包括发现LRRK2在帕金森病发病机制中的作用的新见解，以及开发一种新的生物标记物(exosome pS1292-LRRK2)，可以预测LRRK2突变携带者的帕金森病表现。成功预测LRRK2突变携带者将继续发展为帕金森病，将有助于未来LRRK2导向疗法的临床试验设计。最后，我们预测新的生物标记物exosome pS1292-LRRK2可能有助于将经历PD症状快速进展的特发性PD患者与那些有更多良性疾病病程的患者分层。识别预后不良的帕金森病患者将有助于医生做出治疗选择和新的神经保护疗法的临床试验设计。