Discipline of Genetics, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia.
Hum Mol Genet. 2014 Feb 1;23(3):602-17. doi: 10.1093/hmg/ddt448. Epub 2013 Sep 18.
PRESENILIN1 (PSEN1) is the major locus for mutations causing familial Alzheimer's disease (FAD) and is also mutated in Pick disease of brain, familial acne inversa and dilated cardiomyopathy. It is a critical facilitator of Notch signalling and many other signalling pathways and protein cleavage events including production of the Amyloidβ (Aβ) peptide from the AMYLOID BETA A4 PRECURSOR PROTEIN (APP). We previously reported that interference with splicing of transcripts of the zebrafish orthologue of PSEN1 creates dominant negative effects on Notch signalling. Here, we extend this work to show that various truncations of human PSEN1 (or zebrafish Psen1) protein have starkly differential effects on Notch signalling and cleavage of zebrafish Appa (a paralogue of human APP). Different truncations can suppress or stimulate Notch signalling but not Appa cleavage and vice versa. The G183V mutation possibly causing Pick disease causes production of aberrant transcripts truncating the open reading frame after exon 5 sequence. We show that the truncated protein potentially translated from these transcripts avidly incorporates into very stable Psen1-dependent higher molecular weight complexes and suppresses cleavage of Appa but not Notch signalling. In contrast, the truncated protein potentially produced by the P242LfsX11 acne inversa mutation has no effect on Appa cleavage but, unexpectedly, enhances Notch signalling. Our results suggest novel hypotheses for the pathological mechanisms underlying these diseases and illustrate the importance of investigating the function of dominant mutations at physiologically relevant expression levels and in the normally heterozygous state in which they cause human disease rather than in isolation from healthy alleles.
早老素 1（PSEN1）是引起家族性阿尔茨海默病（FAD）突变的主要基因座，也在脑 Pick 病、家族性痤疮反转和扩张型心肌病中发生突变。它是 Notch 信号转导和许多其他信号通路以及蛋白切割事件的关键促进剂，包括从淀粉样β（Aβ）前体蛋白（APP）产生 Amyloidβ（Aβ）肽。我们之前报道过，干扰斑马鱼 PSEN1 同源物转录本的剪接会对 Notch 信号转导产生显性负效应。在这里，我们将这项工作扩展到表明，人 PSEN1（或斑马鱼 Psen1）蛋白的各种截断对 Notch 信号转导和斑马鱼 Appa（人类 APP 的一个同源物）的切割有明显不同的影响。不同的截断可以抑制或刺激 Notch 信号转导，但不能切割 Appa，反之亦然。可能导致 Pick 病的 G183V 突变导致异常转录物的产生，这些转录物在 5 号外显子序列后截断开放阅读框。我们表明，潜在翻译这些转录物的截短蛋白会强烈并入依赖 Psen1 的非常稳定的高分子量复合物中，并抑制 Appa 的切割，但不影响 Notch 信号转导。相比之下，由 P242LfsX11 痤疮反转突变潜在产生的截短蛋白对 Appa 的切割没有影响，但出人意料的是，它增强了 Notch 信号转导。我们的结果为这些疾病的病理机制提供了新的假说，并说明了在生理相关表达水平和正常杂合状态下研究显性突变功能的重要性，而不是将其与健康等位基因分离。
