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.

摘要 淀粉样蛋白聚集体是阿尔茨海默病（AD）的病理学标志，但它们在AD中的作用 并且靶向这些聚集体的治疗效果仍然存在争议。人们对它的影响知之甚少 这些蛋白质所处的蛋白质组环境，或者是什么使它们在特定位点聚集， 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这种共同作用。 沉积许多其他蛋白质，但目前还没有直接的连锁事件，解释 菌斑组成。该领域目前所处的困境严重突出了缺乏适当的 结构机制模型，以了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子决定了特异性疾病 入会仪式 在这个项目中，VIB弗兰德斯生物技术研究所的开关实验室将对选择性的 研究AD中β淀粉样蛋白（Aβ）和tau蛋白的淀粉样蛋白聚集的机制，并将对AD中β淀粉样蛋白（A β）和tau蛋白的聚集进行系统性研究。 基于聚集的序列和结构特异性的潜在相互作用伙伴。这种系统性 蛋白质组范围的筛选是基于这样的假设，即淀粉样蛋白聚集是由特异性的 Aβ和tau内的聚集倾向区（APR）与聚集倾向序列片段的相互作用 在其他蛋白质中的背景蛋白质组。 他们已经开发出一种独特的计算管道来模拟异型相互作用， 识别细胞中淀粉样蛋白修饰物的能力。该项目将研究异型淀粉样蛋白在体内的影响， 在小鼠模型中的相互作用和命中，将在分子上详细分析Aβ和tau蛋白的聚集， 被相互作用所改变。 目标1将运行计算机屏幕，特别强调与选择性可接受性相关的已知因素。的 计算筛选将使用与APR具有序列同源性的序列片段的全原子建模 以鉴定可能修饰Aβ或tau聚集的其他脑表达蛋白。目标2将 在细胞模型中筛选全长蛋白质，以确定能够修饰Aβ淀粉样蛋白聚集的候选蛋白 和tau蛋白在一个复杂的生物学背景下。目的3将鉴定通过表达在体内具有作用的修饰剂。 小鼠模型中最有效的修饰蛋白，以研究对淀粉样蛋白聚集开始和程度的影响。 Aβ和tau的病理学。对于目标2和3中确定的最有前途的改性剂，目标4将阐明 所选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学方法， 阐明这些相互作用如何改变Aβ和tau的淀粉样蛋白形成。

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