LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease
LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease
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DOI：
10.1073/pnas.0605461103
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发表时间：
2006-11-21
影响因子：
11.1
通讯作者：
Stone, David J.
中科院分区：
文献类型：
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作者：
Majercak, John;Ray, William J.;Stone, David J.
罕见的家族性阿尔茨海默病 (AD) 被认为是由 β-淀粉样前体蛋白 (APP) 中 Aβ42 肽的蛋白水解产量增加引起的。尽管更常见的迟发性 AD (LOAD) 的发病机制尚不清楚，但 BACE1（一种裂解 APP 生成 A beta 42 N 末端的蛋白酶）在 LOAD 患者中更加活跃，表明淀粉样蛋白产生加工的增加也可能导致散发性疾病。使用高通量 siRNA 筛选技术，我们评估了 15,200 个基因在 A beta 42 分泌中的作用，并鉴定出富含亮氨酸的重复跨膜 3 (LRRTM3) 作为促进 BACE1 进行 APP 加工的神经元基因。靶向 LRRTM3 的 siRNA 可抑制培养细胞和原代神经元中 A beta 40、A beta 42 和 sAPP beta（BACE1 裂解产生的 N 端 APP 片段）的分泌高达 60%，而过表达会增加 A beta 的分泌。 LRRTM3 几乎只在神经系统中表达，包括 AD 期间受影响的区域，例如齿状回。此外，LRRTM3 映射到与 LOAD 和升高的血浆 A beta 42 相关的 10 号染色体区域，并且在结构上与包括 NOGO 受体（神经元再生和 APP 处理的抑制剂）在内的神经元受体家族相似。因此，LRRTM3 是 AD 的功能和位置候选基因，并且鉴于其受体样结构和限制表达，它是一个潜在的治疗靶点。
Rare familial forms of Alzheimer's disease (AD) are thought to be caused by elevated proteolytic production of the A beta 42 peptide from the beta-amyloid-precursor protein (APP). Although the pathogenesis of the more common late-onset AD (LOAD) is not understood, BACE1, the protease that cleaves APP to generate the N terminus of A beta 42, is more active in patients with LOAD, suggesting that increased amyloid production processing might also contribute to the sporadic disease. Using high-throughput siRNA screening technology, we assessed 15,200 genes for their role in A beta 42 secretion and identified leucine-rich repeat transmembrane 3 (LRRTM3) as a neuronal gene that promotes APP processing by BACE1. siRNAs targeting LRRTM3 inhibit the secretion of A beta 40, A beta 42, and sAPP beta, the N-terminal APP fragment produced by BACE1 cleavage, from cultured cells and primary neurons by up to 60%, whereas overexpression increases A beta secretion. LRRTM3 is expressed nearly exclusively in the nervous system, including regions affected during AD, such as the dentate gyrus. Furthermore, LRRTM3 maps to a region of chromosome 10 linked to both LOAD and elevated plasma A beta 42, and is structurally similar to a family of neuronal receptors that includes the NOGO receptor, an inhibitor of neuronal regeneration and APP processing. Thus, LRRTM3 is a functional and positional candidate gene for AD, and, given its receptor-like structure and restricted expression, a potential therapeutic target.