An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease.
An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease.
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DOI：
10.15252/emmm.201404438
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发表时间：
2015-02
影响因子：
11.1
通讯作者：
Taniguchi N
中科院分区：
文献类型：
--
作者：
Kizuka Y;Kitazume S;Fujinawa R;Saito T;Iwata N;Saido TC;Nakano M;Yamaguchi Y;Hashimoto Y;Staufenbiel M;Hatsuta H;Murayama S;Manya H;Endo T;Taniguchi N
β - 位点淀粉样前体蛋白裂解酶 - 1（BACE1）是产生淀粉样β（Aβ）肽的关键蛋白酶，是阿尔茨海默病（AD）的主要药物靶点。然而，有人担心抑制BACE1也可能影响一些生理功能。在此，我们表明BACE1被平分型N - 乙酰葡糖胺（GlcNAc）修饰，这是一种在大脑中高度表达的糖修饰，并且证明AD患者的BACE1上平分型GlcNAc水平更高。对缺乏合成平分型GlcNAc的生物合成酶GnT - III（Mgat3）的基因敲除小鼠的分析显示，在这些小鼠中BACE1对Aβ前体蛋白（APP）的裂解减少，导致Aβ斑块减少和认知功能改善。这种修饰的缺失使BACE1导向晚期内体/溶酶体，在那里它与APP的共定位减少，从而加速溶酶体降解。值得注意的是，其他BACE1底物，如CHL1和接触蛋白 - 2，在GnT - III缺陷小鼠中正常裂解，这表明平分型GlcNAc对BACE1的作用对APP是选择性的。考虑到GnT - III缺陷小鼠仍然健康，GnT - III可能是AD治疗的一个新颖且有前景的药物靶点。
The β-site amyloid precursor protein cleaving enzyme-1 (BACE1), an essential protease for the generation of amyloid-β (Aβ) peptide, is a major drug target for Alzheimer's disease (AD). However, there is a concern that inhibiting BACE1 could also affect several physiological functions. Here, we show that BACE1 is modified with bisecting N-acetylglucosamine (GlcNAc), a sugar modification highly expressed in brain, and demonstrate that AD patients have higher levels of bisecting GlcNAc on BACE1. Analysis of knockout mice lacking the biosynthetic enzyme for bisecting GlcNAc, GnT-III (Mgat3), revealed that cleavage of Aβ-precursor protein (APP) by BACE1 is reduced in these mice, resulting in a decrease in Aβ plaques and improved cognitive function. The lack of this modification directs BACE1 to late endosomes/lysosomes where it is less colocalized with APP, leading to accelerated lysosomal degradation. Notably, other BACE1 substrates, CHL1 and contactin-2, are normally cleaved in GnT-III-deficient mice, suggesting that the effect of bisecting GlcNAc on BACE1 is selective to APP. Considering that GnT-III-deficient mice remain healthy, GnT-III may be a novel and promising drug target for AD therapeutics.
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影响因子：
3
作者：
Akasaka-Manya, Keiko;Manya, Hiroshi;Endo, Tamao
通讯作者：
Endo, Tamao
影响因子：
64.5
作者：
Dennis JW;Nabi IR;Demetriou M
通讯作者：
Demetriou M
影响因子：
4.8
作者：
Kang, Eugene L.;Cameron, Andrew N.;Tesco, Giuseppina
通讯作者：
Tesco, Giuseppina
影响因子：
4.3
作者：
Akasaka-Manya, Keiko;Manya, Hiroshi;Endo, Tamao
通讯作者：
Endo, Tamao
影响因子：
4.8
作者：
Hitt, Brian;Riordan, Sean M.;Vassar, Robert
通讯作者：
Vassar, Robert