Truncating presenilin mutations and their effects on gamma-secretase activity, tau and beta-catenin

阿尔茨海默病（AD）和癌症在人类痛苦和它对社会和经济造成的护理负担方面越来越重要。散发性（非遗传性）AD是痴呆症最常见的形式，但了解甚少。PRESENILIN基因PSEN1和PSEN2是导致遗传性AD的突变的主要位点，也与癌症有关。使用斑马鱼胚胎模型，我们发现，与目前的想法相反，截短早老蛋白的突变有效地抑制正常的早老蛋白活性。(They所谓的负主导（dominant negative）。这意味着它们对胚胎发育是致命的，并解释了为什么在遗传性AD中从未发现过此类突变。值得注意的是，这一发现只能使用斑马鱼胚胎中可能的微妙形式的基因操作。我们的工作还建立了第一个PSEN2非凋亡（非细胞死亡）功能的测定，并表明PSEN2活性被截短的PSEN1抑制。这是PSEN1和PSEN2蛋白在正常生理表达水平下可能相互作用的第一个迹象。早老素活性的丧失促进癌症。截短的早老素蛋白可以由癌细胞中常见的基因转录错误（异常转录剪接）产生。这表明通过异常剪接（或癌前细胞中的突变）产生的截短的显性负性形式的早老素可能在肿瘤形成中很常见。拟议的研究将确定PSEN1的区域，其中截断导致显性负活性。这将允许进一步检查早老素在参与AD和癌症的细胞信号通路中的作用。我们还将研究与年龄相关的人类细胞早老素截短在散发性AD形成中的作用。这可能揭示了这种疾病的遗传和散发形式之间的共同分子联系。

Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have discovered that, contrary to current thought, mutations that truncate presenilin proteins potently suppress normal presenilin activity. (They are so called, dominant negatives). This means that they are lethal for embryo development and explains why such mutations have never been found in inherited AD. Notably, this discovery could only be made using a subtle form of gene manipulation that is possible in zebrafish embryos. Our work has also established the first assay for the non-apoptotic (non-cell death) function of PSEN2 and has shown that PSEN2 activity is inhibited by truncated PSEN1. This is the first indication of possible interaction between PSEN1 and PSEN2 proteins at normal physiological expression levels. Loss of presenilin activity promotes cancer. Truncated presenilin proteins could be produced by errors in gene transcription (aberrant transcript splicing) common in cancerous cells. This suggests that truncated, dominant negative forms of presenilin produced through aberrant splicing (or mutation in precancerous cells) might be common in tumour formation. The proposed research will define the region of PSEN1 in which truncation leads to dominant negative activity. This will allow further examination of the role of presenilins in the cell signalling pathways involved in AD and cancer. We will also investigate the role that age-related truncation of presenilins in human cells can play in the formation of sporadic AD. This may reveal a common molecular link between the inherited and sporadic forms of this disease.