Proteostasis in Neurodegenerative Disease

描述（由申请人提供）：蛋白质聚集是神经退行性疾病的主要病理标志，如阿尔茨海默病（AD）和额颞叶变性（FTLD）；某些形式的错误折叠蛋白（低聚物或淀粉样肽或tau的内含物）在诱导产生症状的一系列事件中的作用在很大程度上是无可争议的。虽然最初“一种蛋白质聚集，一种原因，一种疾病”的假设是主流思想，但在过去十年中，人们已经清楚地认识到，这些疾病在任何一种特定疾病中都存在多种蛋白质聚集，更具异质性。在大多数情况下，混合病理涉及被确定为本质上易受自种子错误折叠和聚集的蛋白质（TDP-43就是一个例子）。这些混合病理出现的机制尚不清楚，主要的假设是一种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性网络的功能产生负面影响

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.