Proteostasis and secondary proteinopathy in AD and FTD

AD 和 FTD 中的蛋白质稳态和继发性蛋白质病

基本信息

批准号：
9052107
负责人：
DAVID R BORCHELT
金额：
$ 30.75万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052107
关键词：
Affect Age-Months Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid deposition Amyloidosis Animals Antibodies Appearance Autophagocytosis Autopsy Back Bioinformatics Biological Models Brain Brain Pathology Caenorhabditis elegans Cell physiology Central Nervous System Diseases Data Analyses Deposition Development Disease Doxycycline Energy Metabolism Environment Enzymes Event Evolution Foundations Frontotemporal Dementia Health Heterogeneity Homeostasis Human Human Pathology Huntington gene Individual Invertebrates Laboratories Link Memory Loss Modeling Mus Neurofibrillary Tangles Neurons Output Pathologic Pathology Pathway interactions Patients Pick Disease of the Brain Process Proteins Proteomics Quality Control Reagent Secondary to Senile Plaques Severities Sirolimus Solubility Staging System Tauopathies Transcriptional Regulation Transgenes Work amyloid pathology base corticobasal degeneration genetic association insight loss of function metabolomics mouse model mutant network dysfunction neurodegenerative phenotype novel novel marker promoter protein TDP-43 protein aggregate protein expression protein misfolding superoxide dismutase 1 synuclein tau Proteins tau expression tau mutation

项目摘要

DESCRIPTION (provided by applicant): One of the major gaps in our understanding of the evolution of Alzheimer's disease is how the deposition of amyloid triggers tauopathy. Moreover, it is now widely recognized that it is common for the CNS of individuals with a neurodegenerative phenotype to develop multiple pathologic abnormalities. The basis for the preponderance of mixed pathology is poorly understood. We hypothesize that insults that compromised function of the proteostasis network may lay the foundation for the development of mixed proteinopathies. The basic concept here is that high levels of misfolded proteins produce an added burden on the proteostatic network by occupying various activities required to dissociate such aggregates and degrade the misfolded proteins. This concept was first uncovered in C. elegans models, where the expression of proteins that produce intracellular inclusions leads to the secondary misfolding of by-stander proteins that are particularly dependent upon the proteostatic network. Recently, we have extended this concept to mammalian model systems. In proteomic studies of brain from mice with high levels of Alzheimer-amyloidosis, Drs. Xu and Borchelt identified a number of cytosolic proteins that appeared to lose solubility - a finding that is consistent with the hypothesis that amyloid deposition can, by some manner, impinge on the function of the proteostatic network to cause "secondary" misfolding. The Lewis laboratory also recently found that two independent lines of mice that model tau pathology also develop cytoplasmic TDP-43 immunoreactive inclusion pathology. Thus, in our mouse models, we are beginning to uncover evidence that the accumulation of one misfolded protein, can by some manner, impact on the folding of others. Our central hypothesis is that these secondary pathologies are the consequence, at least in part, of a disturbance in the cellular protein quality control network, or proteostasis network, to cause collateral misfolding. In the present application, we propose 3 Aims that seek to determine the contribution of proteostatic network dysfunction to the evolution of AD-related pathology. Aim 1 will create a novel paradigm in which mutant tau expression is induced in a preexisting environment of amyloid pathology and disturbed proteostatic function. Aim 2 will determine how the mixed pathology of AD may synergize to produce by-stander misfolding and whether the severity of such misfolding produces functional deficits in critical cellular processes (e.g. energy metabolism). Aim 3 will determine whether augmentation of proteostatic networks mitigates by-stander misfolding. Collectively, these studies will provide new insight into how AD-related pathology impacts CNS protein homoeostasis and whether augmentation of the network in later stages of disease may provide significant benefit.

描述（由申请人提供）：我们对阿尔茨海默氏病进化的理解中的主要差距之一是淀粉样蛋白的沉积如何引发 tau 蛋白病。此外，现在人们广泛认识到，具有神经退行性表型的个体的中枢神经系统通常会出现多种病理异常。人们对混合病理占主导地位的基础知之甚少。我们假设损害蛋白质稳态网络功能的损伤可能为混合蛋白质病的发展奠定基础。这里的基本概念是，高水平的错误折叠蛋白质通过占据解离此类聚集物和降解错误折叠蛋白质所需的各种活动，对蛋白质静态网络产生额外的负担。这个概念首先在秀丽隐杆线虫模型中被发现，其中产生细胞内内含物的蛋白质的表达导致特别依赖于蛋白质抑制网络的旁观者蛋白质的二次错误折叠。最近，我们将这个概念扩展到哺乳动物模型系统。在对患有高水平阿尔茨海默淀粉样变性小鼠大脑的蛋白质组学研究中，博士。 Xu和Borchelt鉴定了许多似乎失去溶解度的胞质蛋白——这一发现与淀粉样蛋白沉积可以通过某种方式影响蛋白抑制网络的功能从而导致“二次”错误折叠的假设相一致。 Lewis 实验室最近还发现，模拟 tau 病理学的两个独立小鼠系也出现细胞质 TDP-43 免疫反应性包涵体病理学。因此，在我们的小鼠模型中，我们开始发现证据表明一种错误折叠蛋白质的积累可以通过某种方式影响其他蛋白质的折叠。我们的中心假设是，这些继发性病理学至少部分是细胞蛋白质质量控制网络或蛋白质稳态网络紊乱的结果，导致侧枝错误折叠。在本申请中，我们提出了 3 个目标，旨在确定蛋白质抑制网络功能障碍对 AD 相关病理学演变的贡献。目标 1 将创建一个新的范例，在该范例中，在淀粉样蛋白病理学和蛋白质抑制功能扰乱的预先存在的环境中诱导突变 tau 表达。目标 2 将确定 AD 的混合病理学如何协同作用以产生旁观者错误折叠，以及这种错误折叠的严重程度是否会在关键细胞过程中产生功能缺陷（例如能量代谢）。目标 3 将确定蛋白质静态网络的增强是否可以减轻旁观者的错误折叠。总的来说，这些研究将为 AD 相关病理学如何影响 CNS 蛋白质稳态以及疾病后期网络的增强是否可以提供显着益处提供新的见解。