Mammalian asparagine endopeptidase (AEP) is a cysteine protease that cleaves its protein substrates on the C-terminal side of asparagine residues. Converging lines of evidence indicate that AEP may be involved in the pathogenesis of several neurological diseases, including Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. AEP is activated in the aging brain, cleaves amyloid precursor protein (APP) and promotes the production of amyloid-β (Aβ). We renamed AEP to δ-secretase to emphasize its role in APP fragmentation and Aβ production. AEP also cleaves other substrates, such as tau, α-synuclein, SET, and TAR DNA-binding protein 43, generating neurotoxic fragments and disturbing their physiological functions. The activity of δ-secretase is tightly regulated at both the transcriptional and posttranslational levels. Here, we review the recent advances in the role of δ-secretase in neurodegenerative diseases, with a focus on its biochemical properties and the transcriptional and posttranslational regulation of its activity, and discuss the clinical implications of δ-secretase as a diagnostic biomarker and therapeutic target for neurodegenerative diseases.

中文翻译：

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神经退行性疾病中的 δ-分泌酶：机制、调节因子和治疗机会。


哺乳动物天冬酰胺内肽酶 (AEP) 是一种半胱氨酸蛋白酶，可在天冬酰胺残基的 C 端侧裂解其蛋白质底物。多种证据表明，AEP 可能参与多种神经系统疾病的发病机制，包括阿尔茨海默病、帕金森病和额颞叶痴呆。 AEP 在衰老的大脑中被激活，裂解淀粉样前体蛋白 (APP) 并促进淀粉样蛋白-β (Aβ) 的产生。我们将 AEP 重命名为 δ-分泌酶，以强调其在 APP 碎片和 Aβ 生成中的作用。 AEP 还会裂解其他底物，例如 tau、α-突触核蛋白、SET 和 TAR DNA 结合蛋白 43，产生神经毒性片段并扰乱其生理功能。 δ-分泌酶的活性在转录和翻译后水平上受到严格调节。在此，我们回顾了δ-分泌酶在神经退行性疾病中作用的最新进展，重点关注其生化特性及其活性的转录和翻译后调节，并讨论了δ-分泌酶作为诊断生物标志物和治疗的临床意义。神经退行性疾病的目标。