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）：“预测帕金森病表型中的外泌体LRRK2”对预测帕金森氏病（PD）易感性和进展的定量生物标志物的迫切需要。这种生物标志物将有助于开发缓慢或停止疾病的新疗法。 PD具有明显的遗传成分，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），在某些人群中携带着病态的错义突变。 LRRK2通过全基因组关联研究进一步与PD敏感性有关。致病性LRRK2突变上调LRRK2激酶活性，并增加自动磷酸化残基丝氨酸S1292（PS1292）的水平。在我们以前的项目“ PDBP中的探索实验室和分析项目”（U18 NS082132）中，我们将精力集中在临床样本中分析和测量LRRK2上。我们发现可以在来自脑脊柱液（CSF）和尿液的外泌体馏分中检测并定量自动磷酸化的LRRK2（PS1292-LRK2）。我们发现来自pd的G2019S-LRK2突变载体的尿外泌体中PS1292-LRK2的升高水平（〜5倍）。在G2019S-LRK2突变载体中，PS1292-LRK2水平成功预测了临床PD表现。我们进一步分析了阿拉巴马大学伯明翰·帕金森氏病生物标志物计划（UAB PDBP）的大量病例和对照组中的PS1292-LRK2（n = 160），发现患者的PS1292-LRRK2水平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CSF纯化的外泌体PS1292-LRK2的潜力，在预测早期和中期特发性PD病例以及LRRRK2突变载体中的PD敏感性和进展方面。项目成功将包括发现新的见解对LRRK2在PD发病机理中的作用以及新型生物标志物（外部PS1292-LRRK2）的发展，该标志物可能预测LRRK2突变载体中PD的表现。 LRRK2突变载体的成功预测将继续开发PD，这将有助于对LRRK2定向疗法的将来的临床试验设计。最后，我们预测，新型的生物标志物外壳PS1292-LRRK2可能有助于分层特发性PD患者，这些患者将从具有更多良性疾病课程的患者中经历PD症状的快速发展。鉴定预后不良的PD病例将有助于医生做出治疗选择和针对新型神经保护疗法的临床试验设计。