Chaperone-mediated signaling in Alzheimer's disease

阿尔茨海默病（AD）的主要病理组成部分是神经元缠结（NFT）的形成 由过度磷酸化的tau（p-tau）组成，这是一个与神经变性密切相关的过程。加快 去除这些p-tau种类可能是高度相关的治疗策略。我们已经证明， Hsp 90的ATP酶活性不依赖于热休克的从头伴侣转录而降解p-tau 因子-1;然而，已经描述了tau蛋白的多种降解途径，这些可能适用于 同样重要的是关于潜在的tau积累的机制。因此我们开始 研究组成型伴侣复合物和新的独立途径的机制 以便于去除异常的p-tau。Hsp 90复合体通常与 各种可互换的组分（即E3泛素连接酶、脯氨酰异构酶等）， 底物的完全或部分再折叠，或其降解。虽然有几个组件具体涉及 在p-tau降解中，我们发现重折叠的共分子伴侣P23也可以调节 tau生物学，而不是采取行动，以防止其退化。这种相互作用将提供新的证据， 发病机制部分是由于固有的线性tau蛋白的错误折叠，这一事件可能是由 淀粉样蛋白增生此外，独特的小热休克蛋白家族可能以完全不同的方式发挥作用 以促进tau蛋白降解。因此，在这个奖项的指导阶段，我计划发展我的技能， 将遗传物质施用至小鼠脑，集中于病毒介导的shRNA和 兴趣该阶段的主要焦点将是通过AAV将Hsp 27递送至tau转基因小鼠以确定Hsp 27的表达。 这对tau蛋白病理学的影响。在奖项的后期，我们将调查两部小说 调节tau蛋白降解的途径;一个主要由Hsp 27介导，另一个由成熟的 热休克蛋白90复合物。我们计划进一步研究Hsp 90通路的分叉可能对 AD发病机制，探索如何恢复性共伴侣蛋白不仅可以防止tau蛋白降解， 促进其聚集。此外，我们计划研究淀粉样蛋白可能在促进tau蛋白中的作用。 功能障碍，要么损害或促进其加工通过伴侣网络，也许提供了一个新的 AD发病机制 公开描述 阿尔茨海默病是由于异常蛋白质积累在大脑中的首要危险因素 年龄。我们的目标是确定这些蛋白质积累的方式， 治疗阿尔茨海默病的新靶点具体而言，我们打算集中精力消除 一旦蛋白质开始积累，就可以逆转疾病的进展 而不是阻止它。

A primary pathological component of Alzheimer's disease (AD) is the formation of neurofibrillary tangles (NFT) composed of hyper-phosphorylated tau (p-tau), a process closely linked to neurodegeneration. Expediting the removal of these p-tau species may be a highly relevant therapeutic stratagem. We have shown that inhibition of the ATPase activity of Hsp90 degrades p-tau independent of de novo chaperone transcription by heat shock factor-1; however multiple degradation pathways have been described for the tau protein, and these may hold equal importance with regard to the mechanisms underlying tau accumulation. Therefore we have begun investigating the mechanisms used by both the constitutive chaperone complex and novel independent pathways of degradation to facilitate the removal of abnormal p-tau. The Hsp90 complex typically works in concert with various interchangeable components (i.e. E3 ubiquitin ligases, prolyl isomerases, etc) culminating in either complete or partial re-folding of the substrate, or its degradation. While several components specifically involved in p-tau degradation have been identified, we have found that the re-folding co-chaperone, P23, may also regulate tau biology, acting rather to prevent its degradation. This interaction would provide new evidence that AD pathogenesis is due in part to the mis-folding of the inherently linear tau protein, an event perhaps precipitated by amyloid accretion. In addition, the unique family of small heat shock proteins may act in an entirely different way to promote tau degradation. Therefore, in the mentored phase of this award, I plan to develop my skills in the administration of genetic material to the murine brain, focusing on viral mediated delivery of shRNAs and genes of interest. A major focus of this phase will be the delivery of the Hsp27 by AAV to tau transgenic mice to determine the impact that this would have on tau pathology. In the latter phase of the award, we will investigate two novel pathways that regulate tau degradation; one mediated primarily by Hsp27 and the other mediated by the mature Hsp90 complex. We plan to further investigate the impact that the bifurcation of the Hsp90 pathway might have on AD pathogenesis, exploring how restorative co-chaperones might not only prevent tau degradation, but may also promote its aggregation. In addition, we plan to examine the role that amyloid may have in promoting tau dysfunction to either impair or facilitate its processing via the chaperone network, perhaps providing a novel mechanism of AD onset. PUBLIC DESCRIPTION Alzheimer's disease is the result of abnormal protein accumulation in the brain with the primary risk factor being age. Our goal is to identify ways in which these proteins accumulate and perhaps identify new drug targets for the treatment of Alzheimer's disease. Specifically, we intend to focus on the removal of the proteins once they have already started to accumulate in an effort to reverse the progression of the disease rather than prevent it.