delta-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities

• Type of Material: Article
• Authors: Zhentao Zhang, Emory University; Ye Tian, Wuhan University; Keqiang Ye, Emory University
• Language: English
• Date: 2020-01-06
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s40035-019-0179-3
• Title of Journal or Parent Work: TRANSLATIONAL NEURODEGENERATION
• Volume: 9
• Issue: 1
• Start Page: 1
• End Page: 1
• Grant/Funding Information: This work is supported by grants from the National Institute of Health (RF1, AG051538; RO1, NS105982) to K. Ye, and grants from the National Natural Science Foundation of China (No. 81822016, 81771382, and 81571249) to Z. Zhang.
• Keywords: RANDOMIZED-TRIAL; ALZHEIMERS-DISEASE; TDP-43; PRECURSOR PROTEIN; TAU; Alzheimer's disease; OSTEOCLAST FORMATION; Neurosciences & Neurology; BINDING-PROTEIN-BETA; Life Sciences & Biomedicine; ASPARAGINE ENDOPEPTIDASE; MOUSE LEGUMAIN; MAMMALIAN LEGUMAIN; CLEAVAGE; Parkinson's disease; Science & Technology; TrkB; C/EBP beta; Neurosciences; AEP
• Research Categories: Biology, Neuroscience; Psychology, Cognitive

Abstract

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.