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）：我们对阿尔茨海默氏病进化的理解的主要差距之一是淀粉样蛋白触发tauopathy的沉积。此外，现在已广泛认识到，具有神经退行性表型的个体的中枢神经系统是发展多种病理异常的。混合病理占优势的基础知之甚少。我们假设侮辱损害了蛋白质之间的网络功能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通过占用分离此类骨料并降解错误折叠蛋白所需的各种活动，从而在蛋白抑制网络上增加负担。该概念首先是在秀丽隐杆线虫模型中发现的，其中产生细胞内夹杂物的蛋白质的表达导致副蛋白质蛋白质的次要错误折叠，这些蛋白质尤其依赖于蛋白质静态网络。最近，我们将此概念扩展到了哺乳动物模型系统。在高水平的阿尔茨海默 - 淀粉样变性的小鼠的脑研究中，博士。 Xu和Borchelt鉴定出似乎失去溶解度的许多胞质蛋白 - 这一发现与淀粉样蛋白沉积可以通过某种方式构成蛋白质静态网络的功能以引起“次级”错误折叠的发现是一致的。刘易斯实验室最近还发现，模拟tau病理学的两种独立的小鼠也会发展出细胞质TDP-43免疫反应性包容性病理。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的积累可以通过某种方式影响对他人的折叠产生影响。我们的核心假设是，这些次要病理至少部分是在细胞蛋白质质量控​​制网络或蛋白质量的网络中发生干扰的结果 导致抵押错误折叠。在本应用中，我们提出了3个目标，旨在确定蛋白抑制性网络功能障碍对与AD相关病理的演变的贡献。 AIM 1将创建一个新的范式，其中突变的tau表达在淀粉样病理学和蛋白抑制功能的先前存在的环境中诱导。 AIM 2将确定AD的混合病理如何协同化以产生副折叠的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）。 AIM 3将确定蛋白抑制网络的增强是否会减轻副标的错误折叠。总的来说，这些研究将提供有关与广告相关的病理如何影响CNS蛋白同种异体的新见解，以及在疾病后期是否增加网络的增强可能会带来可观的好处。