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

• 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
• 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' 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

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）：我们对阿尔茨海默病演变的理解中的一个主要空白是淀粉样蛋白的沉积如何引发tau病。此外，现在广泛认识到，具有神经退行性表型的个体的中枢神经系统发生多种病理异常是常见的。混合病理占优势的基础尚不清楚。我们假设损害蛋白质平衡网络功能的损伤可能为混合性蛋白质病的发展奠定了基础。这里的基本概念是，高水平的错误折叠蛋白质通过占用解离这些聚集体和降解错误折叠蛋白质所需的各种活动，对蛋白质静止网络产生额外的负担。这一概念最初是在秀丽隐杆线虫模型中发现的，在线虫模型中，产生细胞内包涵体的蛋白质的表达导致特别依赖于蛋白质抑制网络的备用蛋白的二次错误折叠。最近，我们将这一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的小鼠进行的大脑蛋白质组学研究中，Xu和Borchelt发现了一些似乎失去溶解度的细胞质蛋白——这一发现与淀粉样蛋白沉积可以通过某种方式影响蛋白质静止网络的功能从而导致“继发性”错误折叠的假设相一致。Lewis实验室最近还发现，模拟tau病理的两种独立的小鼠系也发生细胞质TDP-43免疫反应性包涵病理。因此，在我们的小鼠模型中，我们开始发现一种错误折叠蛋白质的积累可以以某种方式影响其他蛋白质的折叠的证据。我们的中心假设是，这些继发性病理是细胞蛋白质质量控制网络或蛋白质静止网络受到干扰的结果，至少部分是如此