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Bisecting GlcNAc modification stabilizes BACE1 protein under oxidative stress conditions
Yasuhiko Kizuka1, Miyako Nakano2, Shinobu Kitazume3
1Disease Glycomics Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Centre for Systems Chemical Biology, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
The Biochemical Journal
|October 16, 2015
Summary
Bisecting N-acetylglucosamine (GlcNAc) stabilizes beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1) under oxidative stress. This glycan modification protects BACE1 from degradation, increasing amyloid-beta production in Alzheimer's disease.
Area of Science:
- Neuroscience
- Biochemistry
- Glycobiology
Background:
- Beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1) is crucial for amyloid-beta (Aβ) production in Alzheimer's disease (AD).
- Oxidative stress is known to up-regulate BACE1, but the underlying mechanisms remain unclear.
- N-acetylglucosaminyltransferase-III (GnT-III) modifies BACE1 with bisecting N-acetylglucosamine (GlcNAc), and its deficiency accelerates BACE1 lysosomal degradation.
Purpose of the Study:
- To investigate the role of bisecting GlcNAc in stabilizing BACE1 protein under oxidative stress conditions.
- To elucidate the mechanism by which bisecting GlcNAc influences BACE1 degradation and Aβ production.
Main Methods:
- Analysis of BACE1 and bisecting GlcNAc levels in mouse brains with Aβ deposition.
- Prooxidant treatment of wild-type and GnT-III knockout mouse embryonic fibroblasts (MEFs) to assess BACE1 expression and degradation.
- Liquid chromatography/electrospray ionization/mass spectrometry (LC/ESI/MS) analysis of BACE1 glycopeptides to map bisecting GlcNAc modification sites.
- Site-directed mutagenesis of BACE1 N-glycosylation sites to evaluate the impact on bisecting GlcNAc modification and degradation.
Main Results:
- Aβ deposition in mouse brains correlates with increased oxidative stress, BACE1 levels, and bisecting GlcNAc.
- Prooxidant treatment increased BACE1 in wild-type MEFs but decreased it in GnT-III knockout MEFs, indicating accelerated lysosomal degradation.
- Bisecting GlcNAc was mapped to two N-glycosylation sites on BACE1 (Asn153 and Asn223).
- Mutations at these sites abolished bisecting GlcNAc modification and largely prevented the enhanced degradation observed in GnT-III knockout cells.
- Traumatic brain injury-induced BACE1 up-regulation was significantly suppressed in the brains of Mgat3 knockout mice.
Conclusions:
- Bisecting GlcNAc modification stabilizes BACE1 protein against oxidative stress-induced degradation.
- This glycan-mediated stabilization contributes to increased BACE1 levels and Aβ generation under pathological conditions.
- Targeting bisecting GlcNAc modification presents a novel therapeutic strategy for reducing Aβ production in Alzheimer's disease.
