VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, and Leuven Institute for Neurodegenerative Diseases (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium.
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Neuron. 2016 Apr 20;90(2):410-6. doi: 10.1016/j.neuron.2016.03.010.
Recently it was proposed that the familial Alzheimer's disease (FAD) causing presenilin (PSEN) mutations PSEN1-L435F and PSEN1-C410Y do not support the generation of Aβ-peptides from the amyloid precursor protein (APP). This challenges the amyloid hypothesis and disagrees with previous work showing that PSEN1 FAD causing mutations generate invariably long Aβ and seed amyloid. We contrast here the proteolytic activities of these mutant PSEN alleles with the complete loss-of-function PSEN1-D257A allele. We find residual carboxy- and endo-peptidase γ-secretase activities, similar to the formerly characterized PSEN1-R278I. We conclude that the PSEN1-L435F and -C410Y mutations are extreme examples of the previously proposed "dysfunction" of γ-secretase that characterizes FAD-associated PSEN. This Matters Arising paper is in response to Xia et al. (2015), published in Neuron. See also the response by Xia et al. (2016), published in this issue.
最近有人提出，家族性阿尔茨海默病（FAD）引起的早老素（PSEN）突变 PSEN1-L435F 和 PSEN1-C410Y 并不支持从淀粉样前体蛋白（APP）生成 Aβ-肽。这对淀粉样蛋白假说提出了挑战，也与之前的研究结果相矛盾，此前的研究表明，PSEN1 FAD 引起的突变总是会产生长的 Aβ并引发淀粉样蛋白沉淀。在这里，我们将这些突变 PSEN 等位基因的蛋白水解活性与完全丧失功能的 PSEN1-D257A 等位基因进行对比。我们发现存在残留的羧基和内肽酶 γ-分泌酶活性，类似于以前表征的 PSEN1-R278I。我们得出结论，PSEN1-L435F 和 -C410Y 突变是以前提出的“功能障碍”的极端例子，这种功能障碍是 FAD 相关 PSEN 的特征。本文是对 Xia 等人（2015 年）在神经元杂志上发表的论文的回应。也可以参考 Xia 等人（2016 年）在本期杂志上发表的回应。
