Chaperone-mediated signaling in Alzheimer's disease

阿尔茨海默病(AD)的主要病理成分是神经原纤维缠结(NFT)的形成 由过度磷酸化的tau(p-tau)组成，这是一个与神经退化密切相关的过程。加快了 去除这些p-tau可能是一种高度相关的治疗策略。我们已经证明，抑制 热休克诱导Hsp90的ATPase活性不依赖于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，这些途径可能适用 对tau积累的机制同样重要。因此，我们已经开始 探讨构造性伴侣复合体和新的独立通路的作用机制 以促进非正常p-tau的去除。Hsp90复合体通常与 各种可互换的成分(即E3泛素连接酶、脯氨酰异构酶等)最终以 底物完全或部分重新折叠，或其降解。虽然有几个组件特别涉及 在p-tau降解已被鉴定的情况下，我们发现重新折叠的辅伴蛋白P23也可能调节 牛磺酸生物，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，证明AD 发病的部分原因是固有的线性tau蛋白的错误折叠，这一事件可能是由 淀粉样变。此外，独特的小热休克蛋白家族可能会以完全不同的方式发挥作用 以促进牛磺酸的降解。因此，在这个奖项的指导阶段，我计划在 向小鼠脑内注射遗传物质，重点是病毒介导的shRNAs和 利息。这一阶段的一个主要焦点将是通过aav将hsp27传递给tau转基因小鼠以确定 这将对tau病理产生的影响。在奖项的后一阶段，我们将调查两部小说 调节tau降解的途径；一条主要由Hsp27介导，另一条由成熟蛋白介导 HSP90复合体。我们计划进一步研究Hsp90途径的分叉可能对 AD发病机制，探索恢复性辅助伴侣如何不仅可以防止tau降解，还可以 促进其聚合。此外，我们计划研究淀粉样蛋白在促进tau中可能起到的作用。 功能障碍，通过伴侣网络损害或促进其处理，或许提供了一种新的 AD的发病机制。 公开描述 阿尔茨海默病是蛋白质在大脑中异常堆积的结果，是主要的危险因素 年事已高。我们的目标是确定这些蛋白质积累的方式，或许还能识别新药。 阿尔茨海默病的治疗目标。具体地说，我们打算重点删除 蛋白质一旦开始积累，就会努力逆转疾病的发展。 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.