Post-translational Modifications of Proteins in Parkinson?s disease

描述(由申请人提供)：帕金森氏病(PD)通常与认知障碍有关，这一点越来越明显。病理评估一再证明，帕金森病患者的痴呆(PD-D)与大脑皮质路易小体(Lbs)的形成或阿尔茨海默病(AD)的变化(存在神经原纤维缠结(NFTS)和老年斑(SPS))有关。众所周知，LBS、NFTS和SPS的形成分别与1-突触核蛋白(SNCA)、tau和A？的沉积有关。然而，这些关键蛋白的变化与PD-D的发展关系尚不清楚。我们假设帕金森病患者认知障碍的发展与SNCA、tau和A？的独特翻译后修饰(PTM)有关，并且PTM具有异构体/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开发的一项功能，使用了各种最先进的蛋白质组学技术。此外，由于PD-D的发展可能涉及不仅仅是SNCA、tau和A？的细胞过程，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丰富，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(有针对性和无偏见的分析)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。确认和验证的标志物，无论是在脑脊液或血浆中，然后可以作为高度敏感和特异的多重免疫分析(XMAP)的基础，用于识别有认知缺陷风险的PD患者。为了实现这些目标，人们设计了四个特定的目标：1)在临床确诊的伴有和不伴有痴呆的帕金森病患者中，在病理受累的脑区寻找与帕金森病发生相关的独特蛋白质。2)从临床上证实和验证在不同阶段痴呆和非痴呆活体受试者腰椎脑脊液中发现的独特蛋白质。3)从临床上证实和验证在不同阶段痴呆患者和非痴呆患者的血浆中，脑组织中发现的独特蛋白质。4)建立用于检测帕金森病患者认知损害的xMAP检测方法。公共卫生相关性：本项目调查与帕金森氏症患者认知损害发展相关的潜在生物标志物。识别这些标志物可以增加帕金森患者患痴呆症的治疗窗口，痴呆症与死亡率、照顾者负担和疗养院入院风险有关。

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.