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: 10039820
• 负责人: Ignazio Cali
• 金额: $ 11.97万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039820
• 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.

项目摘要/摘要 多种致病蛋白的同时出现是在获得和特发性中经常发生的事件 神经退行性疾病。淀粉样蛋白β（Aβ）和tau病理在阿尔茨海默氏病中共存； α-突触核蛋白 和帕金森氏病的Aβ；焦油DNA结合蛋白43和tau在皮质型变性中。 最近，我研究了医源性克鲁兹菲尔特 - jakob病（ICJD），这是一种通过感染获得的人prion病， 和慢性创伤性脑病/创伤后应激障碍（CTE/PTSD），一种神经退行性的 继发于重复创伤的条件。 ICJD的一部分以致病性或疾病的共同出现 相关的原始蛋白（PRPD）和Aβ，我两者都提出了人与人之间的传播造成的。 同样，CTE/PTSD的子集具有PRPD和致病性TAU（TAUD）。多重的共存 神经退行性疾病中的致病蛋白尚未完全了解。 在此K99/r00中，i建议研究ICJD中共发生蛋白质的分子特征， 零星CJD（SCJD）和CTE/PTSD以及动物模型中。医源性CJD和CTE/PTSD提供 研究非时代相关多蛋白神经变性的机制的独特优势。三 提出了相互关联的特定目标。特定的目标1着重于PRPD和Aβ的构象性能 与Aβ-中的PRPD特征相比，ICJD和SCJD病例的聚集体 负ICJD和SCJD；晚期发作阿尔茨海默氏病将提供经典Aβ的控制数据。具体目标 2涉及从CTE/PTSD病例收获的PRPD和TAUD的构象特征，这两种蛋白质病 与相应的CTE/PTSD病例相比，受TAUD影响但不影响PRPD；病毒疾病的病例将服用 作为经典的PRPD控制。这些研究提出的方法完善了基于质谱的方法 评估共存致病蛋白的构象特征的方法，通过 蛋白质错误折叠循环扩增（PMCA）技术和细胞毒性测定，采用原发性神经元 文化。特定目的3通过传播的 关于新型转基因小鼠模型共同表达人类细胞PRP和人类的条件 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，包括日期和传播途径，病原体的相互作用的存在 在疾病表型形成的传播和阶段期间的蛋白质。我相信这些 利用新描述的条件的研究包括沿 借助新型的实验模型，将在重要领域产生重要且需要的信息 研究。通过这些研究以及在我的两个主要导师Drs的专门指导下。 Surewicz 和朱，以及我心理委员会的其他成员，我将获得所需的经验和技能 成为成功的独立研究者和神经退行性领域的领导者。