Synergistic Interaction of amyloid-beta and alpha-synuclein in Lewy body Dementia

路易体痴呆中β淀粉样蛋白和α-突触核蛋白的协同相互作用

• 批准号: 10686893
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 287.18万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686893
• 关键词: Acceleration; Address; Alleles; Amyloid beta-Protein; Apolipoprotein E; Arizona; Autopsy; Biochemistry; Biometry; Brain; Cell Nucleus; Cell model; Cells; Characteristics; Clinic; Clinical; Cryoelectron Microscopy; Data; Dedications; Development; Diagnostic; Disease; Disease Progression; Doctor of Philosophy; Etiology; Filament; Funding; Future; Genetic; Goals; Heterogeneity; Institution; Intervention; Lewy Body Dementia; Lewy body pathology; Lipids; Molecular; Molecular Structure; Molecular and Cellular Biology; Neurons; Other Genetics; Pathogenesis; Pathogenicity; Pathologic; Pathway Analysis; Pathway interactions; Patients; Process; Proteins; Proteomics; Qualifying; Reporting; Research; Research Personnel; Research Project Grants; Resources; Saint Jude Children' s Research Hospital; Sampling; Standardization; Structural Biochemistry; Structure; Symptoms; Technical Expertise; Techniques; Toxic effect; Transcript; Work; alpha synuclein; apolipoprotein E-4; brain tissue; clinically relevant; dementia risk; drug discovery; druggable target; endophenotype; genetic risk factor; insight; interdisciplinary approach; lipidomics; multidisciplinary; neuropathology; neurotoxicity; novel; phosphoneuroprotein 14; prevent; protein aggregation; structural biology; therapy development; transcriptomics

The overarching goal of this proposed Lewy body dementia (LBD) center without walls (CWOW) is to understand synergistic interactions of amyloid-beta (Aβ) and alpha-synuclein (α-syn) and to determine how genetic risk factors, such as apolipoprotein E4, contribute to LBD pathogenesis. Using well-characterized postmortem brain tissue from the Mayo Clinic Brain Bank, CWOW investigators will probe genetics, transcriptomics, proteomics, lipidomics, structure, biochemistry, and function of Aβ and α-syn species in LBD. The CWOW has an Administrative Core and a Neuropathology and Biochemistry Core, as well as four research projects. The Administrative Core will provide fiscal and scientific oversight, management, and reporting functions. The Neuropathology and Biochemistry Core will provide neuropathologically well- characterized LBD brain samples and quantitative endophenotypes to all projects. The research projects are led by highly qualified investigators who focus on complementary and fundamental aspects of LBD. Project 1 will explore genetic correlates of clinical and pathologic heterogeneity of LBD, as well as cell-specific transcript data from single nuclei sequencing to build network analyses, which will provide insights into underlying disease mechanisms. Project 2 will identify and validate proteins and low-abundant bioactive lipid species in LBD brains that may be important to the unique pathologic signature of LBD. Project 3 will use state-of-the–art cryo-EM techniques to characterize the native and molecular structures of α-syn and Aβ filaments in LBD brain to generate novel insight into the etiology, toxicity and spreading of protein aggregates in this disease. Project 4 will isolate and characterize Aβ and α-syn subspecies from postmortem brains and use cellular models to reveal mechanistic insight into toxic pathways contributing to disease pathogenesis. We envision that, at the conclusion of the funding period, we will have made significant progress towards understanding unique structural and molecular features of LBD and how genetics and interactions between Aβ and α-syn contribute to the unique symptoms, progression, and underlying pathology of LBD.

拟议的路易体痴呆 (LBD) 无壁中心 (CWOW) 的总体目标是了解淀粉样蛋白 - β (Aβ) 和 α-突触核蛋白 (α-syn) 的协同相互作用，并确定载脂蛋白 E4 等遗传风险因素如何影响 LBD 发病机制。 CWOW 研究人员将利用 Mayo Clinic 脑库中经过充分表征的死后脑组织，探索 LBD 中 Aβ 和 α-syn 物种的遗传学、转录组学、蛋白质组学、脂质组学、结构、生物化学和功能。 CWOW 设有行政核心、神经病理学和生物化学核心，以及四个研究项目。行政核心将提供财政和科学监督、管理和报告职能。神经病理学和生物化学核心将为所有项目提供神经病理学上明确表征的 LBD 大脑样本和定量内表型。这些研究项目由高素质的研究人员领导，他们专注于 LBD 的补充和基本方面。项目 1 将探索 LBD 临床和病理异质性的遗传相关性，以及来自单核测序的细胞特异性转录数据以构建网络分析，这将提供对潜在疾病机制的见解。项目 2 将鉴定并验证 LBD 大脑中的蛋白质和低丰度生物活性脂质物质，这些物质可能对 LBD 的独特病理特征很重要。项目 3 将使用最先进的冷冻电镜技术来表征 LBD 大脑中 α-syn 和 Aβ 丝的天然结构和分子结构，从而对该疾病中蛋白质聚集体的病因学、毒性和传播产生新的见解。项目 4 将从死后大脑中分离和表征 Aβ 和 α-syn 亚种，并使用细胞模型揭示导致疾病发病机制的毒性途径的机制。我们预计，在资助期结束时，我们将在了解 LBD 独特的结构和分子特征以及 Aβ 和 α-syn 之间的遗传学和相互作用如何影响 LBD 的独特症状、进展和潜在病理学方面取得重大进展。

项目成果

Analysis of monohexosyl alkyl (alkenyl)-acyl glycerol in brain samples by shotgun lipidomics.

• DOI: 10.1016/j.aca.2020.07.016
• 发表时间: 2020-09-08
• 期刊: Analytica chimica acta
• 影响因子: 6.2
• 作者: Wang C;Wang J;Qin C;Han X
• 通讯作者: Han X

Clinical and pathological characteristics of later onset multiple system atrophy.

• DOI: 10.1007/s00415-022-11067-1
• 发表时间: 2022-08
• 期刊: Journal of neurology
• 影响因子: 6

Late-onset mania in autopsy-confirmed Lewy body disease: A rare symptom of prodromal dementia with Lewy bodies?

尸检证实的路易体病迟发性躁狂：路易体前驱痴呆的罕见症状？

• DOI: 10.1111/bdi.13246
• 发表时间: 2022
• 期刊: Bipolar disorders
• 影响因子: 5.4
• 作者: Koga,Shunsuke;Sekiya,Hiroaki;Martin,NicholasB;Dickson,DennisW
• 通讯作者: Dickson,DennisW

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.

• DOI: 10.1016/j.cell.2022.02.026
• 发表时间: 2022-04-14
• 期刊: CELL
• 影响因子: 64.5
• 作者: Chang, Andrew;Xiang, Xinyu;Wang, Jing;Lee, Carolyn;Arakhamia, Tamta;Simjanoska, Marija;Wang, Chi;Carlomagno, Yari;Zhang, Guoan;Dhingra, Shikhar;Thierry, Manon;Perneel, Jolien;Heeman, Bavo;Forgrave, Lauren M.;DeTure, Michael;DeMarco, Mari L.;Cook, Casey N.;Rademakers, Rosa;Dickson, Dennis W.;Petrucelli, Leonard;Stowell, Michael H. B.;Mackenzie, Ian R. A.;Fitzpatrick, Anthony W. P.
• 通讯作者: Fitzpatrick, Anthony W. P.

Diagnosing multiple system atrophy: current clinical guidance and emerging molecular biomarkers.

• DOI: 10.3389/fneur.2023.1210220
• 发表时间: 2023
• 期刊: FRONTIERS IN NEUROLOGY
• 影响因子: 3.4
• 作者: Goolla, Meghana;Cheshire, William P.;Ross, Owen A.;Kondru, Naveen
• 通讯作者: Kondru, Naveen