Post-translational Modifications of Proteins in Parkinson?s disease

6.项目总结/摘要 越来越清楚的是，帕金森病（PD）通常与认知障碍有关。 病理学评估反复证明PD患者痴呆（PD-D）与以下因素相关： 路易体（LB）的形成或阿尔茨海默病的变化（存在神经元缠结（NFT）和 老年斑（SP））。众所周知，LB、NfT和SP的形成与以下因素有关： 分别沉积<$-突触核蛋白（SNCA）、tau和A <$。然而，这些关键蛋白质的变化是 与PD-D发展的关系尚不清楚。我们假设认知能力的发展 PD损伤与SNCA、tau和A？的独特翻译后修饰（PTM）相关， PTM是同种型/物种特异性的，以及疾病阶段特异性的。因此， 该建议是将SNCA、tau和A？的各种亚型/种类的PTM表征为PD的函数， 使用各种最先进的蛋白质组学技术进行D开发。随着PD-D的发展， 可能涉及细胞过程，而不仅仅是SNCA，tau和A？，目的是发现生物标志物 我们还将使用高通量蛋白质组学技术， 具有独特的PTM（糖基化）的蛋白质组，其在体液中高度富集，即携带大量蛋白质的蛋白质。 可能成为PD-D的生物标志物。这两种分析（有针对性和无偏见的分析）将应用于 最初经病理学证实的脑组织，随后在脑脊液中证实和验证 (CSF)和血浆。确认和验证的标志物，无论是在CSF或血浆中，然后可以 作为用于识别PD患者的高灵敏度和特异性多重免疫测定（xMAP）的基础 有认知缺陷的风险 为实现这些目标，制定了四个具体目标： 1)在确诊的PD中，确定病理受累脑区中PD-D发展的独特蛋白质 临床上有痴呆和无痴呆的病例。 2)确认和验证从活体受试者获得的腰椎CSF中脑组织中发现的独特蛋白质 在临床上有和没有痴呆的不同阶段。 3)确认和验证从活体受试者获得的血浆中脑组织中发现的独特蛋白质， 临床上有和没有痴呆的不同阶段。 4)建立用于检测PD 7中认知障碍的xMAP测定。项目叙述 该项目研究了与发展相关的潜在生物标志物， 帕金森患者的认知障碍。可以增加对这些制造商的识别 帕金森氏症患者的治疗窗口处于发展痴呆症的风险中， 与死亡率、照顾者负担和入住疗养院的风险相关。

6. Project Summary/Abstract 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 ¿-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. Project Narrative 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.