Membrane Trafficking Laboratory, Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium.
Biochem Soc Trans. 2010 Dec;38(6):1474-8. doi: 10.1042/BST0381474.
AD (Alzheimer's disease) is a neurodegenerative disease characterized by a gradual loss of neurons and the accumulation of neurotoxic Aβ (amyloid β-peptide) and hyperphosphorylated tau. The discovery of mutations in three genes, PSEN1 (presenilin 1), PSEN2 (presenilin 2) and APP (amyloid precursor protein), in patients with FAD (familial AD) has made an important contribution towards an understanding of the disease aetiology; however, a complete molecular mechanism is still lacking. Both presenilins belong to the γ-secretase complex, and serve as the catalytic entity needed for the final cleavage of APP into Aβ. PSEN only functions within the γ-secretase complex through intra- and inter-molecular interactions with three other membrane components, including nicastrin, Aph-1 (anterior pharynx defective-1) and Pen-2 (PSEN enhancer-2). However, although the list of γ-secretase substrates is still expanding, other non-catalytic activities of presenilins are also increasing the complexity behind its molecular contribution towards AD. These γ-secretase-independent roles are so far mainly attributed to PSEN1, including the transport of membrane proteins, cell adhesion, ER (endoplasmic reticulum) Ca(2+) regulation and cell signalling. In the present minireview, we discuss the current understanding of the γ-secretase-independent roles of PSENs and their possible implications in respect of AD.
AD（阿尔茨海默病）是一种神经退行性疾病，其特征是神经元逐渐丧失和神经毒性 Aβ（淀粉样 β-肽）和过度磷酸化 tau 的积累。在 FAD（家族性 AD）患者中发现三个基因 PSEN1（早老素 1）、PSEN2（早老素 2）和 APP（淀粉样前体蛋白）的突变，对了解疾病发病机制做出了重要贡献；然而，仍然缺乏完整的分子机制。两种早老素都属于 γ-分泌酶复合物，是 APP 最终切割成 Aβ 所需的催化实体。PSEN 仅通过与另外三个膜成分（包括尼卡斯特林、Aph-1（前咽缺陷 1）和 Pen-2（PSEN 增强子 2））的分子内和分子间相互作用在 γ-分泌酶复合物中发挥作用。然而，尽管 γ-分泌酶底物的清单仍在不断扩大，但早老素的其他非催化活性也增加了其对 AD 的分子贡献的复杂性。这些 γ-分泌酶非依赖性作用目前主要归因于 PSEN1，包括膜蛋白的运输、细胞黏附、内质网 (ER) Ca(2+) 调节和细胞信号转导。在本次迷你综述中，我们讨论了 PSENs 的 γ-分泌酶非依赖性作用的当前理解及其在 AD 方面的可能意义。
