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

涉及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: 10682584
• 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/10682584
• 关键词: Affect; Alzheimer' s Disease; Amides; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Area; Binding; Biological Assay; Characteristics; Clinical; Codon Nucleotides; Creutzfeldt-Jakob Syndrome; Data; Dedications; 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; 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; Post-Traumatic Stress Disorders; PrP; PrP gene; Prion Diseases; Prions; Probability; 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; 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 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.

项目总结/摘要 一种以上致病蛋白的共同出现在获得性和特发性疾病中是常见的事件。 神经退行性疾病阿尔茨海默病中淀粉样β（Aβ）和tau蛋白病理共存; α-突触核蛋白 和Aβ在帕金森病痴呆中的作用; TAR DNA结合蛋白43和tau在皮质基底节变性中的作用。 最近，我研究了医源性克雅氏病（iCJD），一种通过感染获得的人类朊病毒疾病， 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， 继发于重复性创伤iCJD的一个子集的特点是病原体或疾病的共同出现- 相关朊蛋白（PrPD）和Aβ，我认为这两种疾病都是人传人的结果。 类似地，CTE/PTSD的子集具有PrPD和致病性tau（tauD）。多元共存 神经变性疾病中的致病蛋白尚未完全了解。 在K99/R 00中，我建议研究iCJD中共发蛋白病的分子特征， 散发性CJD（sCJD）和CTE/PTSD以及动物模型中的研究。医源性CJD和CTE/PTSD提供了 对研究非年龄相关的多蛋白神经退行性变的机制具有独特的优势。三 提出了相互关联的具体目标。具体目标1侧重于PrPD和Aβ的构象特性 与Aβ病理学相关的iCJD和sCJD病例的聚集体相比， 阴性iCJD和sCJD;晚发性阿尔茨海默病将提供经典Aβ的对照数据。具体目标 图2涉及从患有两种蛋白质病的CTE/PTSD病例中收集的PrPD和tauD的构象特征 与tauD而非PrPD影响的相应CTE/PTSD病例相比;朊病毒疾病病例将 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 评估共存的致病蛋白的构象特征的方法， 蛋白质错误折叠循环扩增（PMCA）技术和使用原代神经元的细胞毒性测定 cultures.具体目标3进一步剖析了通过蛋白质传播的共同发生的蛋白质病的各个方面。 将上述条件应用于共表达人细胞PrP和人细胞PrP的新型转基因小鼠模型， 淀粉样前体蛋白（APP）。生物测定将检查多蛋白质的关键动力学方面， 神经退行性变，包括传播的时间和途径，病原体相互作用的存在 蛋白质在繁殖过程中和疾病表型形成的阶段。我相信这些加在一起 利用新描述的包括多蛋白和单蛋白病的条件的研究沿着 与新的实验模型，将产生重要的和需要的信息的一个重要领域， research.通过这些研究，并在我的两个主要导师， 和朱先生，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变性领域的领导者。

项目成果

Atypical Case of VV1 Creutzfeldt-Jakob Disease Subtype: Case Report.

• DOI: 10.3389/fneur.2022.875370
• 发表时间: 2022
• 期刊: Frontiers in neurology
• 影响因子: 3.4

Phenotypic diversity of genetic Creutzfeldt-Jakob disease: a histo-molecular-based classification.

• DOI: 10.1007/s00401-021-02350-y
• 发表时间: 2021-10
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Baiardi S;Rossi M;Mammana A;Appleby BS;Barria MA;Calì I;Gambetti P;Gelpi E;Giese A;Ghetti B;Herms J;Ladogana A;Mikol J;Pal S;Ritchie DL;Ruf V;Windl O;Capellari S;Parchi P
• 通讯作者: Parchi P