Proteostasis in Neurodegenerative Disease

描述(申请人提供)：蛋白质聚集是阿尔茨海默病(AD)和额颞叶变性(FTLD)等神经退行性疾病的主要病理特征；某种形式的错误折叠蛋白质(寡聚体或包含β-淀粉样多肽或tau)在诱导产生症状的一连串事件中的作用在很大程度上是毋庸置疑的。虽然最初的“一种蛋白质聚集，一种病因，一种疾病”的假说是占主导地位的思想，但在过去的十年里，很明显，这些疾病是更加异质性的，在任何一种特定的疾病中都存在着多个蛋白质聚集。在大多数情况下，混合病理涉及已被确定为天生易受自身种子错误折叠和聚集影响的蛋白质(TDP-43就是一个例子)。这些混合病理的出现背后的机制还不太清楚，主要的假设是一个错误折叠和聚集的蛋白质的积累对介导蛋白质折叠和降解的活动网络的功能产生了负面影响( 蛋白质平衡网络)。蛋白质平衡功能的丧失被认为是导致易损蛋白质二次错误折叠的原因。我们建议测试这一假设，即阿尔茨海默型淀粉样蛋白和FTLD型神经原纤维缠结的积累可以诱导二级报告蛋白的聚集，而在转基因小鼠模型中，二级报告蛋白天生容易错误折叠和聚集。表达该报告的小鼠，包括一种融合了黄色荧光蛋白(SODG85R：YFP)的超氧化物歧化酶1变体，其水平略低于启动自身种子聚集的阈值，将与发展为阿尔茨海默病样淀粉样变性的小鼠和发展为牛角病的小鼠进行杂交。这些小鼠的结果将与表达SODWT：YFP的小鼠的杂交结果进行比较，SODWT：YFP在相同的淀粉样蛋白和肌萎缩症模型中不易聚集。由于提案中解释的原因，我们认为基于SOD1的向量非常适合于本申请所提出的问题。我们在这些实验中的目标是确定一种类型的错误折叠蛋白质在哺乳动物中枢神经系统中的积累是否会降低蛋白稳定功能，以至于系统无法防止其他蛋白质的二次错误折叠，这些蛋白质天生就容易受到自我种子聚集的影响。

DESCRIPTION (provided by applicant): Protein aggregation is a major pathological hallmark of neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD); and the role of some form of misfolded protein (oligomer or inclusion of ¿-amyloid peptide or tau) in inducing a cascade of events that produces symptoms is largely undisputed. Although originally a 'one protein aggregate, one cause, one disease' hypothesis was the dominant ideology, over the last decade it has become clear that these disorders are more heterogeneous with multiple protein aggregates present in any one specific disease. In most cases, the mixed pathology involves proteins that have been identified as intrinsically vulnerable to self-seeded misfolding and aggregation (TDP-43 is an example). The mechanisms that underlie the appearance of these mixed pathologies is poorly understood with a leading hypothesis being that the accumulation of one misfolded and aggregating protein negatively impacts the function of the network of activities that mediate protein folding and degradation (the proteostasis network). Loss of proteostasis function is proposed to lead to secondary misfolding of vulnerable proteins. We propose to test the hypothesis that the accumulation of Alzheimer-type amyloid and FTLD-type neurofibrillary tangles can induce the aggregation of a secondary "reporter" protein that is inherently vulnerable to misfolding and aggregation in transgenic mouse models. Mice that express the reporter, which consists of a variant of superoxide dismutase 1 fused to yellow fluorescent protein (SODG85R:YFP), at levels just below the threshold to initiate self-seeded aggregation, will be crossed with both mice that develop Alzheimer-like amyloidosis and mice that develop tauopathy. Outcomes in these mice will be compared to that of crosses of mice that express SODWT:YFP, which is much less prone to aggregation, with the same amyloid and tauopathy models. For reasons explained within the proposal, we contend that the SOD1-based vectors are well suited for the questions posed by this application. Our goal in these experiments is to establish whether the accumulation of one type of misfolded protein in the mammalian CNS diminishes proteostasis function to such a level that the system fails to prevent the secondary misfolding of other proteins that are intrinsically vulnerable to self-seeded aggregation.