Risk Marker for Parkinson's Disease: Enabling Novel Therapies

描述(由首席研究人员提供)：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930万人，但预防或延缓疾病的药物可能无法及时提供。虽然快速发展的基础研究正在创造一个不断扩大的候选疾病修正疗法的管道，但仅仅依赖不敏感的临床评估已经限制了进展。今天，帕金森病得到临床诊断，只有在黑质中70%的易受攻击的多巴胺神经元丢失后，才会开始疾病修饰药物的临床试验。然而，帕金森病的风险人群，多巴胺神经元不完全丧失的人，对神经保护治疗的反应最快，受益最大。一种简单的实验室生物标记物可以在大多数多巴胺神经元丢失之前识别出发展为帕金森病的高风险个体，与一种新的风险修正疗法相结合，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，但在血细胞中可以检测到这种疾病的DNA、RNA和生化特征。帕金森病、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。一项系统的全基因组表达扫描确定伴侣ST13是早期帕金森病的主要生物标记物。伴侣ST13激活热休克蛋白70，热休克蛋白70抑制1-突触核蛋白的错误折叠和在细胞、酵母和果蝇模型中的毒性。基于微阵列的ST13的测量已经转变为一种基于精确的荧光5‘核酸酶化学的强大的动力学、定量聚合酶链式反应分析。强有力的初步研究表明，低标记物水平与帕金森病风险的升高密切相关。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。与侵入性脑脊液检测或昂贵的成像生物标志物相比，高准确度和重复性的简单实验室检测将具有许多优势。将ST13发展为临床有用的风险标记物的过程将通过严格控制的单中心病例对照研究(哈佛PD生物标记物研究)、全美范围的多中心研究(PROBE)和前瞻性队列研究(PARS)进行。我们的具体目标是：1)描述血液中ST13水平与早期帕金森病风险之间的关系；2)在一项多中心研究中证实ST13水平与帕金森病风险之间关系的有效性和特异性；3)在高危队列中预测未来的帕金森病。如果得到证实，该风险标记物将使旨在预防或延迟帕金森病的新疗法成为可能。公共卫生相关性帕金森氏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930万人，但预防或延缓疾病的药物可能无法及时提供。虽然快速发展的基础研究正在创造一个不断扩大的候选疾病修正疗法的管道，但仅仅依赖不敏感的临床评估已经限制了进展。今天，帕金森病得到临床诊断，只有在黑质中70%的易受攻击的多巴胺神经元丢失后，才会开始疾病修饰药物的临床试验。然而，帕金森病的风险人群，多巴胺神经元不完全丧失的人，对神经保护治疗的反应最快，受益最大。一种简单的实验室生物标记物可以在大多数多巴胺神经元丢失之前识别出发展为帕金森病的高风险个体，与一种新的风险修正疗法相结合，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.