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，帕金森病患者的数量将翻一番，达到930万，但预防或延缓这种疾病的药物可能无法及时问世。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改善疗法管道，但仅仅依赖不敏感的临床评估已经限制了进展。今天，帕金森病被临床诊断出来，只有在黑质中多达70%的易感多巴胺神经元丢失后，才能启动疾病改善药物的临床试验。然而，具有帕金森病风险的个体，多巴胺神经元的完全丧失较少，对神经保护治疗最敏感，也最受益。一种简单的实验室生物标志物可以在大部分多巴胺神经元丧失之前识别出患帕金森病的高风险个体，再加上一种新的风险调节疗法，可能会阻止这种疾病的出现。虽然PD症状反映了优先的神经元死亡，但该疾病的DNA， RNA和生化特征可在血细胞中检测到。PD、多巴胺代谢、线粒体功能和细胞质量控制等标志性生物学过程在血细胞中受到干扰。系统的全基因组表达扫描鉴定出伴侣蛋白ST13是早期PD的主要生物标志物。伴侣蛋白ST13激活热休克蛋白70，在细胞、酵母和苍蝇PD模型中抑制1-突触核蛋白错误折叠和毒性。基于微阵列的ST13测量已经转变为基于精确的荧光5'核酸酶化学的强大动力学，定量聚合酶链反应测定。强有力的初步研究表明，低水平的标志物与帕金森病的风险升高密切相关。我们假设血液中测量的低ST13水平预测PD风险增加。与侵入性脑脊液测试或昂贵的成像生物标志物相比，一个简单的实验室测试具有很高的准确性和重复性，具有许多优势。将ST13发展成为临床有用的风险标志物的过程将从严格控制的单中心病例对照研究（Harvard PD Biomarker study）到全美范围的多中心研究（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ST13水平与早期PD风险之间的关系；2)多中心研究证实ST13水平与PD风险相关性的有效性和特异性；3)预测高危人群的未来PD。如果得到证实，这一风险标志将使设计用于预防或延缓帕金森病的新疗法成为可能。帕金森病是一种进行性神经退行性疾病。到2030年，由于人口老龄化，帕金森病患者的数量将翻一番，达到930万，但预防或延缓这种疾病的药物可能无法及时问世。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改善疗法管道，但仅仅依赖不敏感的临床评估已经限制了进展。今天，帕金森病被临床诊断出来，只有在黑质中多达70%的易感多巴胺神经元丢失后，才能启动疾病治疗药物的临床试验。然而，具有帕金森病风险的个体，多巴胺神经元的完全丧失较少，对神经保护治疗最敏感，也最受益。一种简单的实验室生物标志物可以在大部分多巴胺神经元丧失之前识别出患帕金森病的高风险个体，再加上一种新的风险调节疗法，可能会阻止这种疾病的出现。

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.