Risk Marker for Parkinson's Disease: Enabling Novel Therapies

帕金森病（PD）是一种进行性神经退行性疾病。到2030年， 由于人口老龄化，PD患者将增加一倍，达到930万，但预防药物， 或延迟疾病可能无法及时获得。在基础研究快速发展的同时， 创造一个不断扩大的候选疾病修饰疗法的管道， 不敏感的临床评估阻碍了进展。今天，PD是临床诊断和临床 只有在高达70%的脆弱多巴胺被释放后， 黑质的神经元已经丧失具有PD风险的个体， 然而，多巴胺神经元对神经保护剂的反应最灵敏， 疗法一种简单的实验室生物标志物，可在发生PD之前识别出处于高风险的个体 大多数多巴胺神经元已经丢失，再加上一种新的风险调整治疗方法， 可以防止这种疾病的出现。 虽然PD症状反映了优先的神经元死亡，但其DNA，RNA和生化特征， 疾病可以在血细胞中检测到。帕金森病的标志性生物过程，多巴胺代谢， 线粒体功能和细胞质量控制在血细胞中受到干扰。系统的基因组- 广泛表达扫描鉴定了伴侣蛋白ST 13作为早期PD的主要生物标志物。伴侣 ST 13激活热休克蛋白70，抑制突触核蛋白的错误折叠和细胞毒性， 酵母菌和果蝇模型。基于微阵列的ST 13测量已经转化为 基于精确的荧光5'核酸酶的稳定的动力学定量聚合酶链反应测定 化学.强有力的初步研究表明，低标记水平是强烈和具体的， 与PD风险升高相关。 我们假设血液中ST 13水平低预测PD风险增加。一个简单 高准确性和可重复性的实验室测试将比侵入性CSF具有许多优点 测试或昂贵的成像生物标志物。将ST 13发展为临床有用风险的过程 标记物将通过严格控制的单中心病例对照研究（哈佛PD 生物标志物研究）到美国范围内的多中心研究（PROBE）到前瞻性队列研究（PARS）。我们 具体目标是：1）描述血液中ST 13水平与早期风险之间的关联， 2）证实了ST 13水平与PD风险之间关联的有效性和特异性， 多中心研究; 3）预测高危队列中未来的PD。如果得到确认，风险标记将 实现旨在预防或延迟PD的新疗法。

Parkinson's disease (PD) is a progressive neurodegenerative disease. By 2030 the number of individuals with PD will double to 9.3 million because of aging populations, but medications to prevent, or delay the disease may not become available in time. While rapidly advancing basic research is creating an expanding pipeline of candidate disease-modifying therapeutics, sole reliance on insensitive clinical assessments has curtailed progress. Today, PD is clinically diagnosed and clinical trials of disease-modifying drugs are initiated only after as much as 70% of vulnerable dopamine neurons in the substantia nigra have been lost. Individuals at risk for PD with less complete loss of dopamine neurons, however, would be most responsive to and benefit most from a neuroprotective therapy. A simple laboratory biomarker that identifies individuals at high risk of developing PD before the majority of dopamine neurons has been lost, combined with a novel risk-modifying therapeutic could prevent the disease from ever appearing. While PD symptoms reflect preferential neuronal death, DNA, RNA, and biochemical traits of the disease are detectable in blood cells. The hallmark biological processes of PD, dopamine metabolism, mitochondrial function, and cellular quality-control are perturbed in blood cells. A systematic genome- wide expression scan identified the chaperone ST13 as lead biomarker for early-stage PD. Chaperone ST13 activates heat shock protein 70, which suppresses ¿-synuclein misfolding and toxicity in cellular, yeast, and fly models of PD. The microarray-based measure of ST13 has been transformed into a robust kinetic, quantitative polymerase-chain-reaction assay based on precise, fluorogenic 5' nuclease chemistry. Powerful preliminary studies indicate that low marker levels are strongly and specifically associated with elevated risk of PD. We hypothesize that low ST13 levels measured in blood predict increased risk of PD. A simple laboratory test of high accuracy and reproducibility would have many advantages over invasive CSF tests or expensive imaging biomarkers. The process of developing ST13 into a clinically useful risk marker will advance through a tightly controlled single-center case-control study (Harvard PD Biomarker Study) to a US-wide multi-center study (PROBE) to a prospective cohort study (PARS). Our specific aims are: 1) Delineating the association between ST13 levels in blood and risk of early-stage PD; 2) Confirming the validity and specificity of the association between ST13 levels and risk of PD in a multi-center study; 3) Predicting future PD in an at-risk cohort. If confirmed, the risk marker will enable novel therapies designed to prevent or delay PD.