Risk Marker for Parkinson's Disease: Enabling Novel Therapies

描述（由主要研究者提供）：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患者的数量将增加一倍，达到930万，但预防或延迟疾病的药物可能无法及时获得。虽然快速推进的基础研究正在创造一个不断扩大的候选疾病修饰疗法的管道，但仅仅依赖不敏感的临床评估已经阻碍了进展。今天，只有在黑质中多达70%的脆弱多巴胺神经元丢失后，PD才能被临床诊断出来，疾病改善药物的临床试验才能开始。然而，具有较少多巴胺神经元完全丧失的PD风险的个体将对神经保护治疗反应最大并从中获益最多。一种简单的实验室生物标志物，可以在大多数多巴胺神经元丢失之前识别出患有PD的高风险个体，再加上一种新型的风险调节治疗方法，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，但该疾病的DNA、RNA和生化特征在血细胞中是可检测的。PD、多巴胺代谢、线粒体功能和细胞质量控制的标志性生物过程在血细胞中受到干扰。系统的全基因组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，其抑制1-突触核蛋白错误折叠和PD的细胞、酵母和苍蝇模型中的毒性。基于微阵列的ST 13测量已经转化为基于精确的荧光5'核酸酶化学的稳健的动力学定量聚合酶链反应测定。强有力的初步研究表明，低标志物水平与PD风险升高密切相关。我们假设血液中ST 13水平低预测PD风险增加。一个简单的实验室测试的高准确性和可重复性将有许多优势，侵入性脑脊液测试或昂贵的成像生物标志物。将ST 13开发为临床有用的风险标志物的过程将通过严格对照的单中心病例对照研究（哈佛PD生物标志物研究）推进到美国范围内的多中心研究（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ST 13水平与早期PD风险之间的关联; 2）在多中心研究中证实ST 13水平与PD风险之间关联的有效性和特异性; 3）预测风险队列中未来的PD。如果得到证实，该风险标志物将使旨在预防或延迟PD的新疗法成为可能。帕金森氏病是一种神经退行性疾病。到2030年，由于人口老龄化，PD患者的数量将增加一倍，达到930万，但预防或延迟疾病的药物可能无法及时获得。虽然快速推进的基础研究正在创造一个不断扩大的候选疾病修饰疗法的管道，但仅仅依赖不敏感的临床评估已经阻碍了进展。今天，只有在黑质中多达70%的脆弱多巴胺神经元丢失后，PD才能被临床诊断，疾病改善药物的临床试验才能开始。然而，具有较少多巴胺神经元完全丧失的PD风险的个体将对神经保护治疗反应最大并从中获益最多。一种简单的实验室生物标志物，可以在大多数多巴胺神经元丢失之前识别出患有PD的高风险个体，再加上一种新型的风险调节治疗方法，可以防止这种疾病的出现。

DESCRIPTION (provided by principal investigator): 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 percent 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 1-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. PUBLIC HEALTH RELEVANCE Parkinson's disease 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 percent 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.