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，帕金森氏症患者将增加一倍，达到930万人，但预防药物的使用， 或推迟疾病可能不会及时出现。在快速推进基础研究的同时， 创建一个不断扩大的候选疾病修改疗法的管道，完全依赖于 不敏感的临床评估限制了进展。今天，帕金森病的临床诊断和临床 只有在70%的易受伤害的多巴胺被释放后，才会开始疾病治疗药物的试验 黑质中的神经元已经丢失。患帕金森病风险较低的个人 然而，多巴胺神经元对神经保护的反应最快，受益最大。 心理治疗。一种简单的实验室生物标记物，用于识别以前患帕金森病的高危个体 大多数多巴胺神经元已经丢失，结合一种新的降低风险的疗法 可以防止这种疾病的出现。 虽然帕金森病的症状反映了优先的神经元死亡，但DNA，RNA和生化特征 在血细胞中可以检测到疾病。帕金森病的标志性生物学过程，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。一个系统的基因组- 广泛的表达扫描确定伴侣ST13是早期帕金森病的先导生物标志物。陪护 ST13激活热休克蛋白70，从而抑制突触核蛋白的错误折叠和细胞内的毒性。 酵母菌和帕金森病的苍蝇模型。基于微阵列的ST13措施已经转变为 基于精密荧光5‘核酸酶的动态定量聚合酶链式反应 化学反应。强有力的初步研究表明，低标记水平强烈而特异地 与帕金森病风险升高有关。 我们假设在血液中测量到的低ST13水平预示着帕金森病风险的增加。一个简单的 高准确度和重复性的实验室检测将比侵入性脑脊液有许多优势 测试或昂贵的成像生物标记物。将ST13发展为临床有用风险的过程 马克将通过一项严格控制的单中心病例对照研究(哈佛PD 生物标记物研究)到全美多中心研究(PROBE)，再到前瞻性队列研究(PARS)。我们的 具体目标是：1)描述血液中ST13水平与早期风险之间的联系 帕金森病；2)证实ST13水平与帕金森病发病风险之间关系的有效性和特异性 多中心研究；3)在高危队列中预测未来的帕金森病。如果确认，风险标记将 启用旨在预防或延缓帕金森病的新疗法。

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.