Heterotypic amyloid interactions as modulators of selective cellular vulnerability

异型淀粉样蛋白相互作用作为选择性细胞脆弱性的调节剂

• 批准号: 10707972
• 负责人: Frederic Rousseau
• 金额: $ 52.17万
• 依托单位: FLANDERS INTERUNIV INST BIOTECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707972
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Animals; Binding; Biological; Biological Assay; Biophysics; Biotechnology; Brain; Brain region; Cell Culture System; Cell Line; Cell model; Cells; Complex; Data Set; Deposition; Disease; Event; Fluorescence Resonance Energy Transfer; In Situ; In Vitro; Laboratories; Length; Mediating; Modeling; Molecular; Morphology; Neurons; Pathologic; Pathology; Play; Proteins; Proteome; Proteomics; Recombinant adeno-associated virus (rAAV); Reporter; Reproducibility; Research; Research Project Grants; Role; Running; Sequence Homology; Set protein; Site; Software Tools; Specificity; Statistical Data Interpretation; Structural Models; Structure; Therapeutic; Therapeutic Effect; Viral; abeta accumulation; abeta deposition; amyloid formation; beta amyloid pathology; biophysical techniques; brain cell; candidate identification; computational pipelines; extracellular; in silico; in vivo; mouse model; overexpression; proteostasis; tau Proteins; tau aggregation; vector

ABSTRACT Amyloid aggregates are the defining pathological hallmark of Alzheimer’s Disease (AD), yet the role they play and the therapeutic effect in targeting these aggregates remains controversial. Little is known about the impact of the proteome context in which these proteins reside, or what nucleates their aggregation in specific sites in the brain. Studying the composition of amyloid deposits using proteomic approaches has demonstrated the co- deposition of many other proteins, however currently there is no straightforward chain-of-events that explains plaque composition. The predicament in which the field currently subsists critically highlights the lack of suitable structural-mechanistic models to understand both the causes and consequences of amyloid aggregation in terms of direct molecular interactions, as well as which specific cellular factors determine pathognomonic disease initiation. In this project, the Switch Laboratory in VIB Flanders Institute for Biotechnology will approach the selective amyloid aggregation of beta amyloid (Aβ) and tau in AD mechanistically and will do a systematic search for potential interacting partners based on the sequence- and structure-specificity of aggregation. This systematic and proteome-wide screen is based on the assumption that amyloid aggregation is initiated by the specific interaction of aggregation-prone regions (APRs) within Aβ and tau with aggregation-prone sequence segments in other proteins within the background proteome. They have developed a unique computational pipeline to model heterotypic interactions with sufficient predictive power to identify amyloid modifiers in cells. The project will investigate the in vivo impact of heterotypic amyloid interactions in mouse models and for the hits, will analyze in molecular detail how the aggregation of Aβ and tau is modified by the interactions. Aim 1 will run an in-silico screen with special emphasis on known factors related to selective vulnerably. The computational screen will use all-atom modelling of sequence segments with sequence homology to the APRs of Aβ and tau to identify other brain-expressed proteins that may modify the aggregation of Aβ or tau. Aim 2 will screen full-length proteins in cellular models to identify candidates that can modify amyloid aggregation of Aβ and tau in a complex biological context. Aim 3 will identify modifiers that have an effect in vivo by expressing the most potent modifier proteins in mouse models, to study the impact on aggregation onset and extent of amyloid pathology of Aβ and tau. For the most promising modifiers identified in Aims 2 and 3, Aim 4 will unravel the molecular mechanism of selected heterotypic amyloid interactions use state-of-the-art biophysical methods to elucidate exactly how these interactions change the amyloid formation of Aβ and tau.

抽象的 淀粉样蛋白聚集是阿尔茨海默病 (AD) 的明确病理标志，但它们所发挥的作用 针对这些聚集体的治疗效果仍存在争议。人们对影响知之甚少 这些蛋白质所在的蛋白质组环境，或者是什么使它们在特定位点聚集成核 大脑。使用蛋白质组学方法研究淀粉样蛋白沉积物的组成已经证明了共同作用 许多其他蛋白质的沉积，但是目前还没有直接的事件链可以解释 斑块组成。该领域目前所处的困境凸显了缺乏合适的 结构机制模型，用于理解淀粉样蛋白聚集的原因和后果 直接的分子相互作用，以及哪些特定的细胞因素决定特定的疾病 引发。 在这个项目中，VIB 法兰德斯生物技术研究所的 Switch 实验室将选择性地研究 AD 中 β 淀粉样蛋白 (Aβ) 和 tau 蛋白的淀粉样蛋白聚集机制，并将进行系统研究 基于聚合的序列和结构特异性的潜在相互作用伙伴。这种系统化的 蛋白质组范围的筛选基于这样的假设：淀粉样蛋白聚集是由特定的蛋白质引发的。 Aβ 和 tau 内易聚集区域 (APR) 与易聚集序列片段的相互作用 在背景蛋白质组内的其他蛋白质中。 他们开发了一种独特的计算管道来模拟具有足够预测能力的异型相互作用 识别细胞中淀粉样蛋白修饰剂的能力。该项目将研究异型淀粉样蛋白的体内影响 小鼠模型中的相互作用和命中，将在分子细节上分析 Aβ 和 tau 蛋白的聚集如何 是通过相互作用而改变的。 目标 1 将运行计算机筛选，特别强调与选择性脆弱性相关的已知因素。这 计算屏幕将使用与 APR 具有序列同源性的序列片段的全原子建模 Aβ 和 tau 蛋白，以鉴定其他可能改变 Aβ 或 tau 蛋白聚集的大脑表达蛋白。目标2将 在细胞模型中筛选全长蛋白，以确定可以改变 Aβ 淀粉样蛋白聚集的候选蛋白 和tau蛋白在复杂的生物环境中。目标 3 将通过表达以下内容来识别在体内产生影响的修饰剂： 小鼠模型中最有效的修饰蛋白，用于研究对淀粉样蛋白聚集起始和程度的影响 Aβ 和 tau 的病理学。对于目标 2 和 3 中确定的最有前途的修饰符，目标 4 将揭示 选定异型淀粉样蛋白相互作用的分子机制使用最先进的生物物理方法 准确阐明这些相互作用如何改变 Aβ 和 tau 淀粉样蛋白的形成。

项目成果

TDP-43 pathology is associated with increased tau burdens and seeding.

• DOI: 10.1186/s13024-023-00653-0
• 发表时间: 2023-09-30
• 期刊: MOLECULAR NEURODEGENERATION
• 影响因子: 15.1
• 作者: Tome, Sandra O.;Tsaka, Grigoria;Ronisz, Alicja;Ospitalieri, Simona;Gawor, Klara;Gomes, Luis Aragao;Otto, Markus;von Arnim, Christine A. F.;Van Damme, Philip;van den Bosch, Ludo;Ghebremedhin, Estifanos;Laureyssen, Celeste;Sleegers, Kristel;Vandenberghe, Rik;Rousseau, Frederic;Schymkowitz, Joost;Thal, Dietmar Rudolf
• 通讯作者: Thal, Dietmar Rudolf

Local structural preferences in shaping tau amyloid polymorphism.

• DOI: 10.1038/s41467-024-45429-2
• 发表时间: 2024-02-03
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Louros, Nikolaos;Wilkinson, Martin;Tsaka, Grigoria;Ramakers, Meine;Morelli, Chiara;Garcia, Teresa;Gallardo, Rodrigo;D'Haeyer, Sam;Goossens, Vera;Audenaert, Dominique;Thal, Dietmar Rudolf;Mackenzie, Ian R.;Rademakers, Rosa;Ranson, Neil A.;Radford, Sheena E.;Rousseau, Frederic;Schymkowitz, Joost
• 通讯作者: Schymkowitz, Joost