Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35131 Padua, Italy.
Neuroscience Institute, Italian National Research Council (CNR), Via U. Bassi 58/B, 35131 Padua, Italy.
Cells. 2020 Sep 25;9(10):2166. doi: 10.3390/cells9102166.
Presenilin-2 (PS2) is one of the three proteins that are dominantly mutated in familial Alzheimer's disease (FAD). It forms the catalytic core of the γ-secretase complex-a function shared with its homolog presenilin-1 (PS1)-the enzyme ultimately responsible of amyloid-β (Aβ) formation. Besides its enzymatic activity, PS2 is a multifunctional protein, being specifically involved, independently of γ-secretase activity, in the modulation of several cellular processes, such as Ca signalling, mitochondrial function, inter-organelle communication, and autophagy. As for the former, evidence has accumulated that supports the involvement of PS2 at different levels, ranging from organelle Ca handling to Ca entry through plasma membrane channels. Thus FAD-linked PS2 mutations impact on multiple aspects of cell and tissue physiology, including bioenergetics and brain network excitability. In this contribution, we summarize the main findings on PS2, primarily as a modulator of Ca homeostasis, with particular emphasis on the role of its mutations in the pathogenesis of FAD. Identification of cell pathways and molecules that are specifically targeted by PS2 mutants, as well as of common targets shared with PS1 mutants, will be fundamental to disentangle the complexity of memory loss and brain degeneration that occurs in Alzheimer's disease (AD).
早老素-2（PS2）是三种在家族性阿尔茨海默病（FAD）中主要发生突变的蛋白之一。它构成γ-分泌酶复合物的催化核心——与同系物早老素-1（PS1）共享这一功能——该酶最终负责淀粉样β（Aβ）的形成。除了酶活性之外，PS2 是一种多功能蛋白，特别是在不依赖γ-分泌酶活性的情况下，参与多种细胞过程的调节，如 Ca 信号转导、线粒体功能、细胞器间通讯和自噬。就前者而言，有越来越多的证据表明 PS2 参与了从细胞器 Ca 处理到通过质膜通道的 Ca 内流的不同水平。因此，FAD 相关的 PS2 突变影响细胞和组织生理学的多个方面，包括生物能量学和大脑网络兴奋性。在本研究中，我们总结了 PS2 的主要研究结果，主要是作为 Ca 动态平衡的调节剂，特别强调其突变在 FAD 发病机制中的作用。鉴定 PS2 突变体特异性靶向的细胞途径和分子，以及与 PS1 突变体共享的常见靶点，对于阐明阿尔茨海默病（AD）中发生的记忆丧失和大脑退化的复杂性将是至关重要的。
