Post-translational Modifications of Proteins in Parkinson?s disease

描述（由申请人提供）：越来越清楚的是，帕金森病（PD）通常与认知障碍有关。病理评估反复表明，PD- d患者的痴呆与皮层中路易体（LBs）的形成或阿尔茨海默病的改变（神经原纤维缠结（nft）和老年斑（SPs）的存在）有关。众所周知，LBs、nft和SPs的形成与1-突触核蛋白（SNCA）、tau和A？,分别。然而，这些关键蛋白的变化与PD-D发展的关系尚不清楚。我们假设PD患者认知功能障碍的发生与SNCA、tau和A？ptm具有同种异构体/物种特异性以及疾病阶段特异性。因此，该提案的主要目标之一是表征SNCA， tau和A？作为PD- D发展的功能，使用各种最先进的蛋白质组学技术。此外，由于PD-D的发展可能涉及的细胞过程不仅仅是SNCA、tau和A？为了发现临床上可获得的生物标志物，我们还将使用高通量蛋白质组学技术来表征具有独特的PTM（糖基化）的亚蛋白质组，该亚蛋白质组在体液中高度富集，即具有成为PD-D生物标志物的巨大潜力的蛋白质。这两种分析（目标分析和无偏分析）将首先应用于病理证实的脑组织，然后分别在脑脊液（CSF）和血浆中进行确认和验证。经确认和验证的标志物，无论是在脑脊液还是血浆中，都可以作为高灵敏度和特异性多重免疫测定（xMAP）的基础，用于识别PD患者发生认知缺陷的风险。为了实现这些目标，我们设计了四个特定的目标：1)在临床上确诊的PD患者伴或不伴痴呆的病理相关脑区域中鉴定PD- d发展的独特蛋白质。2)确认并验证从临床有无痴呆的不同阶段活的受试者中获得的腰椎脑脊液脑组织中显示的独特蛋白质。3)在临床有无痴呆的不同阶段活体受试者的血浆中，确认和验证脑组织中发现的独特蛋白质。4)建立检测PD 7认知功能障碍的xMAP方法。公共卫生相关性：本项目调查与帕金森病患者认知障碍发展相关的潜在生物标志物。识别这些制造者可以增加帕金森患者的治疗窗口，这些患者有患痴呆症的风险，这与死亡率、照顾者负担和养老院入院风险有关。

DESCRIPTION (provided by applicant): It has become increasingly clear that Parkinson's disease (PD) is often associated with cognitive impairment. Pathological evaluations have repeatedly demonstrated that dementia in PD patients (PD-D) is associated with either formation of Lewy bodies (LBs) or Alzheimer's changes (presence of neurofibrillary tangles (NfTs) and senile plaques (SPs)) in the cortex. It is well known that formation of LBs, NfTs and SPs are related to deposition of 1-synuclein (SNCA), tau and A?, respectively. However, the changes in these key proteins are not known in relationship to the development of PD-D. We have hypothesized that development of cognitive impairment in PD is associated with unique post-translational modifications (PTMs) of SNCA, tau and A?, and that the PTMs are isoform/species specific, as well as disease stage specific. Thus, one of the major goals of the proposal is to characterize the PTMs of various isoforms/species of SNCA, tau and A? as a function of PD- D development using various state-of-the-art proteomics techniques. Additionally, as development of PD-D likely involves cellular processes beyond just SNCA, tau and A?, for the purpose of discovering biomarkers that are clinically accessible, we will also use a high throughput proteomic technique to characterize a sub- proteome with a unique PTM (glycosylation) that is highly enriched in body fluids, i.e. proteins carrying great potentials to be biomarkers for PD-D. Both analyses (targeted and unbiased profiling) will be applied to pathologically confirmed brain tissues initially, followed by confirmation and validation in the cerebrospinal fluid (CSF) and plasma, respectively. The confirmed and validated markers, whether in CSF or plasma, can then serve as the basis of highly sensitive and specific multiplex immunoassays (xMAP) used to identify PD patients at risk for developing cognitive deficits. Four Specific Aims have been designed to accomplish these goals: 1) Identify proteins unique to the development of PD-D in pathologically involved brain regions in confirmed PD cases with and without dementia clinically. 2) Confirm and validate unique proteins, revealed in brain tissue, in lumbar CSF obtained from living subjects at different stages with and without dementia clinically. 3) Confirm and validate unique proteins, revealed in brain tissue, in plasma obtained from living subjects at different stages with and without dementia clinically. 4) Establish xMAP assays for detecting cognitive impairment in PD 7. PUBLIC HEALTH RELEVANCE: This project investigates the potential biomarkers correlating with the development of cognitive impairment in Parkinson's patients. Identification of these makers can increase therapeutic window for Parkinson's patients at risk for developing dementia that is associated with mortality, caregiver burden and risk for nursing home admission.