Presenilins and γ-Secretase: Structure, Function, and Role in Alzheimer Disease
Presenilins and γ-Secretase: Structure, Function, and Role in Alzheimer Disease
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DOI：
10.1101/cshperspect.a006304
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发表时间：
2012-01-01
影响因子：
5.4
通讯作者：
Wolfe, Michael S.
中科院分区：
文献类型：
--
作者：
De Strooper, Bart;Iwatsubo, Takeshi;Wolfe, Michael S.
早老素最初是作为导致早发性阿尔茨海默病（AD）的错义突变位点而被发现的。随后发现编码的多程膜蛋白是γ分泌酶的催化成分，γ分泌酶是膜包埋的天冬氨酰蛋白酶复合物，负责从淀粉样蛋白前体（APP）产生淀粉样β蛋白（A β）的羧基末端。该蛋白酶复合物还切割多种其他I型整合膜蛋白，最显著的是Notch受体，其信号传导参与许多细胞分化事件。虽然γ-分泌酶是开发疾病修饰AD治疗剂的首要目标，但应避免干扰Notch信号传导。通过γ-分泌酶改变A β产生而不影响Notch蛋白水解和信号传导的化合物已经被鉴定，并且目前处于药物开发管道的不同阶段。
Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD). The encoded multipass membrane proteins were subsequently found to be the catalytic components of gamma-secretases, membrane-embedded aspartyl protease complexes responsible for generating the carboxyl terminus of theamyloid beta-protein (A beta) from the amyloid protein precursor (APP). The protease complex also cleaves a variety of other type I integralmembrane proteins, most notably the Notch receptor, signaling from which is involved in many cell differentiation events. Although gamma-secretase is a top target for developing disease-modifying AD therapeutics, interference with Notch signaling should be avoided. Compounds that alter A beta production by gamma-secretase without affecting Notch proteolysis and signaling have been identified and are currently at various stages in the drug development pipeline.