GGA1 is expressed in the human brain and affects the generation of amyloid β-peptide
GGA1 is expressed in the human brain and affects the generation of amyloid β-peptide
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DOI：
10.1523/jneurosci.1982-06.2006
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发表时间：
2006-12-06
影响因子：
5.3
通讯作者：
Walter, Jochen
中科院分区：
文献类型：
--
作者：
Wahle, Tina;Thal, Dietmar R.;Walter, Jochen
β-淀粉样肽（A β）是阿尔茨海默病（AD）相关老年斑的主要成分，由γ-分泌酶（BACE 1）和γ-分泌酶连续切割β-淀粉样前体蛋白（APP）产生。BACE 1在A β结构域的N末端切割APP，产生膜结合的C末端片段（CTF-β），其随后可被跨膜结构域内的γ-分泌酶切割以释放A β。由于BACE 1启动A β生成，因此它代表了在AD治疗策略中干扰A β生成的潜在靶分子。BACE 1与高尔基体定位的、含有γ-耳的ADP核糖基化因子结合（GGA）蛋白相互作用，所述ADP核糖基化因子结合（GGA）蛋白参与BACE 1的亚细胞运输。在这里，我们表明，GGA 1是优先表达在人脑的神经元。在AD脑中淀粉样斑块周围的活化小胶质细胞中也检测到GGA 1。培养细胞的功能分析表明，GGA 1参与APP的蛋白水解加工。GGA 1或显性负性变体的过表达减少了BACE 1对APP的切割，如CTF-β生成减少所示。重要的是，GGA 1的过表达减少，而RNAi介导的GGA 1抑制增加了A β的分泌。GGA 1对APP加工的调节不依赖于两种蛋白质的直接相互作用。由于BACE 1的总细胞活性不受GGA 1表达的影响，我们的数据表明，BACE 1或其他GGA 1依赖性蛋白的亚细胞运输的变化有助于APP加工和A β生成的变化。因此，GGA蛋白可能参与了AD的发病机制。
The beta-amyloid peptide (A beta) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the beta-amyloid precursor protein (APP) by gamma-secretase (BACE1) and gamma-secretase. BACE1 cleaves APP at the N terminus of the A beta domain, generating a membrane-bound C-terminal fragment (CTF-beta) that can be subsequently cleaved by gamma-secretase within the transmembrane domain to release A beta. Because BACE1 initiates A beta generation, it represents a potential target molecule to interfere with A beta production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, gamma-ear-containing, ADP ribosylation factor-binding (GGA) proteins that are involved in the subcellular trafficking of BACE1. Here, we show that GGA1 is preferentially expressed in neurons of the human brain. GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains. Functional analyses with cultured cells demonstrate that GGA1 is implicated in the proteolytic processing of APP. Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF-beta generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of A beta. The modulation of APP processing by GGA1 is independent of a direct interaction of both proteins. Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular trafficking of BACE1 or other GGA1-dependent proteins contribute to changes in APP processing and A beta generation. Thus, GGA proteins might be involved in the pathogenesis of AD.