Proteostasis and secondary proteinopathy in AD and FTD

描述(由申请人提供)：在我们对阿尔茨海默病的演变的理解中，一个主要的空白是淀粉样蛋白的沉积如何触发肌萎缩症。此外，现在人们普遍认为，具有神经退行性表型的人的中枢神经系统通常会出现多种病理异常。混合病理占优势的基础尚不清楚。我们假设，蛋白平衡网络的功能受损可能为混合性蛋白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据解离这些聚集体和降解错误折叠蛋白质所需的各种活动，对蛋白抑制网络产生额外的负担。这一概念最早是在线虫模型中发现的，在该模型中，产生细胞内包涵体的蛋白质的表达导致旁观者蛋白质的二次错误折叠，这些旁观者蛋白质特别依赖于蛋白抑制网络。最近，我们将这一概念扩展到哺乳动物模型系统。在对阿尔茨海默病-淀粉样变性高水平小鼠大脑的蛋白质组研究中，Xu博士和Borchelt博士发现了许多似乎失去溶解性的细胞质蛋白质--这一发现与以下假设一致：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，导致“继发性”错误折叠。刘易斯实验室最近还发现，模拟tau病理的两个独立品系的小鼠也出现了胞浆TDP-43免疫反应包涵体病理。因此，在我们的小鼠模型中，我们开始发现证据表明，一个错误折叠的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，这些继发性病理至少部分是细胞蛋白质质量控制网络或蛋白平衡网络干扰的结果，以 导致抵押品的错误折叠。在目前的应用中，我们提出了3个目标，试图确定蛋白网络功能障碍在AD相关病理演变中的作用。目的1将创造一种新的范例，其中突变tau的表达是在先前存在的淀粉样蛋白病理和蛋白平衡功能紊乱的环境中诱导的。目标2将确定AD的混合病理如何协同作用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导致关键细胞过程中的功能缺陷 (例如能量代谢)。目标3将确定蛋白质平衡网络的增强是否可以减少旁观者的错误折叠。总而言之，这些研究将为AD相关病理如何影响CNS蛋白稳态以及在疾病后期网络的增强是否可能提供显著益处提供新的见解。

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.