LRRK2 and Other Novel Exosome Proteins in Parkinson's Disease

描述（由申请人提供）：人们普遍认为，在临床人群中，检测与帕金森病（PD）相关的疾病进展和生化途径的措施不足，并且缺乏有效的生物标志物已经阻碍并预计将继续阻碍有效的神经保护（疾病延缓或停止）治疗方法的成功临床试验。遗传和病理研究已经确定了几种与迟发性帕金森病相关的蛋白质，这些蛋白质为了解可能是疾病核心的途径提供了见解。然而，由于疾病易感组织的可用性有限，这些蛋白质很难在PD病例中分析

DESCRIPTION (provided by applicant): It is generally recognized that there are inadequate measures of detecting disease progression and biochemical pathways associated with Parkinson's disease (PD) in clinical populations, and that this lack of effective biomarkers has hindered, and is expected to continue to impede, successful clinical trials for efficacious neuroprotective (disease-retarding or halting) therapeutics. Genetic and pathological studies have identified several proteins linked to late-onset PD, and these proteins have provided insight into pathways that might be central to disease. However, these proteins have been difficult to analyze in PD cases due to the limited availability of disease-susceptible tissue, and studies are usually confined to post-mortem derived specimens. We have made the recent observation that LRRK2, and other proteins linked genetically and pathologically to PD, are detectable in exosomes isolated from human urine samples. Using a multiplex mass spectrometry approach, we can quantify 935 proteins from clinical urine exosome samples, and 140 of these proteins are linked to neurodegeneration by pathway analysis. This proposal seeks to 1) determine whether there are biomarkers associated with PD susceptibility and/or progression in urinary exosome-proteomes derived from PD patients versus controls, and 2) to determine if LRRK2 expression and/or phosphorylation are significantly lowered in the urinary exosomes of individuals treated with the potent LRRK2 kinase inhibitor sunitinib (a multi-kinase inhibitor compound), to establish an assay for on-target effects for future LRRK2 inhibitor clinica trials. Potential biomarkers of interest will be validated in replication cohorts, and the most promising leads will be further explored in future multi-center studies.