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Studying Aggregation in Neurodegenerative Disease Using Synthetic Proteins

使用合成蛋白质研究神经退行性疾病中的聚集

基本信息

批准号：
10339425
负责人：
Ernest James Petersson
金额：
$ 36.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2023-08-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339425
关键词：
Adopted Alzheimer&apos s Disease Amino Acids Amyloid Fibrils Amyloid beta-Protein Binding Cells Chemicals Complex Computer Models Cryoelectron Microscopy Data Dementia Dementia with Lewy Bodies Development Diagnostic Disease Early Diagnosis Exhibits Fluorescence Funding Genetic Polymorphism Image Invaded Investigation Label Measurement Memory Methods Modeling Modification Molecular Molecular Conformation Molecular Structure Monitor Multiple System Atrophy Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurofibrillary Tangles Neurons Parkinson Disease Pathologic Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Play Polymorph Principal Component Analysis Process Protein Dynamics Proteins Publishing Reporting Research Resistance Role Seeds Structure Techniques Testing Therapeutic abeta accumulation alpha synuclein base crosslink cytotoxicity design experimental study imaging agent in silico in vitro Assay inhibitor inhibitor therapy insight molecular modeling monomer neurotoxic novel predictive test preservation prevent protein aggregation protein misfolding protein protein interaction protein structure recruit screening small molecule solid state nuclear magnetic resonance synthetic protein tau Proteins tau aggregation tool unnatural amino acids uptake

项目摘要

Protein misfolding and aggregation to form fibrils are common features of neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, and related dementias such as Dementia with Lewy Bodies and Multiple System Atrophy. Drugs that reverse or block protein aggregation, combined with early diagnosis, provide the prospect for a cure that preserves the patient's memories. To design such drugs and diagnostic agents, one must understand the process of aggregation within neurons and propagation to “infect” new neurons to identify the most relevant targets. In this funding period, we propose to use distance measurements made with fluorescence and crosslinking probes to drive computational models of the misfolding and aggregation of the proteins α-synuclein (αS) and tau. We will model not only monomeric αS and tau, but also aggregated forms that are not amenable to characterization by solid state NMR (ssNMR) or cryo-electron microscopy (cryo-EM). Our computational models will be used to predict the binding of small molecules in order to validate their molecular details and establish their potential for use in the design of inhibitors and diagnostic agents. Our methods can also be used to study different misfolded αS and tau polymorphs, which exhibit different tendencies to form new fibrils and different levels of cytotoxicity. For example, recent investigations of αS, the primary aggregator in Parkinson's Disease, have shown that tau fibrils can be seeded by some conformational forms (“strains”) of αS fibrils, but not others. We will investigate the chemical scale differences in structure between αS strains and the basis for tau fibril seeding by certain strains. This will shed important insight on the pathology of Parkinson's Disease, Dementia with Lewy Bodies, and Multiple System Atrophy; it will also set the stage for investigations of other secondary tau pathologies, such as Aβ-seeded tau aggregates in Alzheimer's Disease.

蛋白质错误折叠和聚集形成原纤维是神经退行性疾病的常见特征，包括阿尔茨海默氏病、帕金森氏病和相关的痴呆症，如路易氏痴呆症身体和多系统萎缩。逆转或阻断蛋白质聚集的药物，结合早期诊断，为保留病人记忆的治疗提供了前景。设计这样的药物，诊断剂，必须了解神经元内的聚集过程和传播“感染” 新的神经元来识别最相关的目标。在本资助期内，我们建议使用距离用荧光和交联探针进行测量，以驱动错误折叠的计算模型以及α-突触核蛋白（αS）和tau蛋白的聚集。我们将不仅模拟单体αS和tau，也包括不适合通过固态NMR（ssNMR）或低温电子（cryo-electron）表征的聚集形式显微镜（cryo-EM）。我们的计算模型将用于预测小分子的结合，以验证其分子细节，并确定其在抑制剂设计和诊断中的应用潜力。剂.我们的方法也可用于研究不同的错误折叠的αS和tau多态性，它们表现出形成新原纤维的不同倾向和不同水平的细胞毒性。例如，最近对 αS是帕金森氏病的主要聚集剂，已经表明tau纤维可以通过一些细胞因子接种。构象形式（“应变”）的αS纤维，但不是其他。我们将调查化学规模的差异， αS菌株之间的结构和某些菌株接种tau纤维的基础。这将使重要对帕金森病、路易体痴呆和多系统萎缩的病理学的见解; 还将为其他继发性tau病理学的研究奠定基础，如Aβ-种子tau聚集体老年痴呆症

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Author Correction: Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein.

作者更正：可溶性α-突触核蛋白的翻译后修饰调节病理性α-突触核蛋白的扩增。

DOI：
10.1038/s41593-023-01474-6
发表时间：
2023
期刊：
Nature neuroscience
影响因子：
25
作者：
Zhang,Shujing;Zhu,Ruowei;Pan,Buyan;Xu,Hong;Olufemi,ModupeF;Gathagan,RonaldJ;Li,Yuanxi;Zhang,Luyan;Zhang,Jasmine;Xiang,Wenxuan;Kagan,EliotMasahiro;Cao,Xingjun;Yuan,Chaoxing;Kim,Soo-Jung;Williams,ChristopherK;Magaki,Shino;
通讯作者：

New strategies for fluorescently labeling proteins in the study of amyloids.