Conformational properties of misfolded protein aggregates in cases involving the co-occurrence of prion disease and Alzehimer's disease or prion disease and CTE

朊病毒病和阿尔茨海默病或朊病毒病和 CTE 同时发生的情况下错误折叠蛋白聚集体的构象特性

• 批准号: 10664201
• 负责人: Ignazio Cali
• 金额: $ 24.9万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664201
• 关键词: Affect; Alzheimer' s Disease; Amides; Amyloid beta-Protein; Animal Model; Area; Binding; Biological Assay; Characteristics; Clinical; Codon Nucleotides; Creutzfeldt-Jakob Syndrome; Data; Deposition; Deuterium; Diagnosis; Disease; Etiology; Event; Experimental Models; Genotype; Harvest; Histidine; Histopathology; Human; Human Amyloid Precursor Protein; Hydrogen; Iatrogenesis; In Vitro; Individual; Infection; Kinetics; Knowledge; Late Onset Alzheimer Disease; Life Expectancy; Light; Mass Spectrum Analysis; Measures; Medical; Mentors; Methodology; Molecular; Molecular Conformation; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson' s Dementia; Pathogenicity; Pathologic; Pathology; Patients; Phase; Phenotype; Play; Post-Traumatic Encephalopathy; Post-Traumatic Stress Disorders; PrP; PrP gene; Prion Diseases; Prions; Procedures; Process; Property; Proteins; Recording of previous events; Reporting; Research; Research Personnel; Role; Route; Secondary to; Tauopathies; Technology; Testing; Time; Toxic effect; Transgenic Mice; Trauma; Traumatic Brain Injury; Variant; Vertebral column; alpha synuclein; base; chronic traumatic encephalopathy; comorbidity; corticobasal degeneration; cytotoxicity; disease phenotype; experience; experimental study; hyperphosphorylated tau; improved; in vivo; member; misfolded protein; mouse model; normal aging; novel; prion-like; protein B; protein TDP-43; protein aggregation; protein misfolding cyclic amplification; skills; synergism; tau Proteins; tau mutation; transmission process

PROJECT SUMMARY/ABSTRACT The co-occurrence of more than one pathogenic protein is a frequent event in acquired and idiopathic neurodegenerative diseases. Amyloid beta (Aβ) and tau pathologies coexist in Alzheimer's disease; α-synuclein and Aβ in Parkinson's disease with dementia; TAR DNA-binding protein 43 and tau in corticobasal degeneration. Recently, I studied iatrogenic Creutzfeldt-Jakob disease (iCJD), a human prion disease acquired by infection, and chronic traumatic encephalopathy/post-traumatic stress disorder (CTE/PTSD), a neurodegenerative condition secondary to repetitive trauma. A subset of iCJD featured the co-occurrence of pathogenic or disease- related prion protein (PrPD) and Aβ, both of which I suggested result from human-to-human transmission. Similarly, a subset of CTE/PTSD harbored PrPD and pathogenic tau (tauD). The co-existence of multiple pathogenic proteins in neurodegenerative conditions has not yet been fully understood. In this K99/R00 I propose to investigate molecular characteristics of co-occurring proteinopathies in iCJD, sporadic CJD (sCJD) and CTE/PTSD as well as in animal models. Iatrogenic CJD and CTE/PTSD offer the unique advantage to study the mechanisms of non-age related multiprotein neurodegeneration. Three interrelated specific aims are proposed. Specific aim 1 focuses on conformational properties of PrPD and Aβ aggregates from cases with iCJD and sCJD associated with Aβ pathology compared to PrPD features in Aβ- negative iCJD and sCJD; late onset Alzheimer's disease will provide control data from classic Aβ. Specific aim 2 deals with conformational features of PrPD and tauD harvested from CTE/PTSD cases with both proteinopathies compared to corresponding CTE/PTSD cases affected by tauD but not PrPD; cases of prion disease will serve as classic PrPD controls. The methodologies proposed for these studies comprise mass spectrometry-based approaches to assess the conformational features of the co-existing pathogenic proteins, seeding kinetics by protein misfolding cyclic amplification (PMCA) technology and cytotoxicity assay employing primary neuronal cultures. Specific aim 3 dissects further aspects of the co-occurring proteinopathies by transmission of the aforementioned conditions to novel transgenic mouse models co-expressing the human cellular PrP and human amyloid precursor protein (APP). The bioassay will examine critical dynamic aspects of multiprotein neurodegeneration, including timing and route of propagation, existence of interactions of the pathogenic proteins during propagation and stages in the formation of the disease phenotype. I believe that together these studies that take advantage of newly-described conditions comprising multi- and single- proteinopathies along with novel experimental models, will generate significant and needed information on an important area of research. Through these studies and under the dedicated guidance of my two primary mentors, Drs. Surewicz and Zhu, and of the other members of my mentoring committee, I will acquire the experience and skills needed to become a successful independent investigator and a leader in the field of neurodegeneration.

项目概要/摘要 超过一种致病蛋白同时出现是获得性和特发性疾病中的常见事件 阿尔茨海默病中，β 淀粉样蛋白 (Aβ) 和 tau 蛋白病理共存； 帕金森病伴痴呆中的 Aβ；皮质基底节变性中的 TAR DNA 结合蛋白 43 和 tau。 最近，我研究了医源性克雅氏病（iCJD），这是一种通过感染获得的人类朊病毒病， 和慢性创伤性脑病/创伤后应激障碍（CTE/PTSD），一种神经退行性疾病 iCJD 的一个子集是继发于重复性创伤的病症，其特征是病原体或疾病同时发生。 相关朊病毒蛋白（PrPD）和 Aβ，我认为这两者都是人际传播的结果。 同样，CTE/PTSD 的一个子集含有 PrPD 和致病性 tau (tauD) 的多种共存。 神经退行性疾病中的致病蛋白尚未完全了解。 在本 K99/R00 中，我建议研究 iCJD 中同时发生的蛋白质病的分子特征， 散发性克雅氏病 (sCJD) 和 CTE/PTSD 以及医源性克雅氏病和 CTE/PTSD 均提供这种情况。 研究非年龄相关多蛋白神经变性机制的独特优势。 提出了相互关联的具体目标。 具体目标 1 重点关注 PrPD 和 Aβ 的构象特性。 与 Aβ 病理相关的 iCJD 和 sCJD 病例的聚合与 Aβ 中的 PrPD 特征相比 阴性 iCJD 和 sCJD；迟发性阿尔茨海默病将提供经典 Aβ 的对照数据。 图 2 涉及从患有两种蛋白病的 CTE/PTSD 病例中收获的 PrPD 和 tauD 的构象特征 与受 tauD 影响但不受 PrPD 影响的相应 CTE/PTSD 病例相比，将起到作用； 作为经典的 PrPD 对照，为这些研究提出的方法包括基于质谱的方法。 评估共存致病蛋白构象特征的方法，通过播种动力学 蛋白质错误折叠循环扩增 (PMCA) 技术和使用初级神经元的细胞毒性测定 具体目标 3 通过传播进一步剖析同时发生的蛋白质病。 共表达人类细胞 PrP 和人类细胞的新型转基因小鼠模型的条件 淀粉样前体蛋白 (APP) 生物测定将检查多蛋白的关键动态方面。 神经变性，包括传播的时间和途径、病原体相互作用的存在 我相信，在传播和形成疾病表型的阶段中，蛋白质是共同作用的。 利用新描述的包括多种和单一蛋白质病的条件的研究 通过新颖的实验模型，将产生关于重要领域的重要且所需的信息 通过这些研究并在我的两位主要导师 Surewicz 博士的专门指导下。 和朱，以及我的指导委员会的其他成员，我将获得所需的经验和技能 成为一名成功的独立研究者和神经退行性疾病领域的领导者。