Risk Marker for Parkinson's Disease: Enabling Novel Therapies

帕金森病的风险标记：实现新疗法

• 批准号: 7912410
• 负责人: CLEMENS R SCHERZER
• 金额: $ 19.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912410
• 关键词: Aging; Basic Science; Biochemical; Biological Assay; Biological Markers; Biological Process; Blood; Blood Cells; Case-Control Studies; Cell physiology; Cessation of life; Chemistry; Classification; Clinical assessments; Cohort Studies; DNA; Diagnosis Clinical Trials; Disease; Dopamine; Future; Heat-Shock Proteins 70; Image; Individual; Kinetics; Laboratories; Lead; Measures; Medicine; Metabolism; Mitochondria; Modeling; Molecular Chaperones; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerases; Polymerase Chain Reaction; Population; Process; Quality Control; Reliance; Reproducibility; Risk; Risk Marker; ST13 gene; Scanning; Specificity; Staging; Substantia nigra structure; Symptoms; Testing; Therapeutic; Time; Toxic effect; United States National Academy of Sciences; Yeasts; base; cohort; dopaminergic neuron; fly; genome-wide; high risk; novel; nuclease; prevent; prospective; synuclein; therapy design; trait

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.

帕金森病（PD）是一种进行性神经退行性疾病。到2030年