A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid-β peptide generation
A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid-β peptide generation
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DOI：
10.1096/fj.09-136457
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发表时间：
2010-01-01
期刊：
影响因子：
4.8
通讯作者：
Kang, David E.
中科院分区：
文献类型：
--
作者：
Lakshmana, Madepalli K.;Chung, John Y.;Kang, David E.
越来越多的生化和遗传学证据表明，淀粉样前体蛋白（APP）衍生的淀粉样β（A β）肽在阿尔茨海默病（AD）发病机制中起着重要作用。我们以前报道过RanBP 9通过将APP/BACE 1/LRP复合物支架在一起来促进A β生成。有趣的是，RanBP 9-Delta 1/N60（残基1-392）缺失突变体与APP/BACE 1/LRP的相互作用比全长RanBP 9强得多。在这项研究中，我们发现RanBP 9-N60，一种与RanBP 9-Delta 1/N60突变体几乎相同的RanBP 9加工形式，与对照组相比，在AD脑中强烈增加。为了评估这种表型的潜在致病后果，我们研究了全长RanBP 9与RanBP 9-Delta 1/N60在HEK 293 T和Neuro-2A细胞中的差异生物学特性。缺乏核定位信号的RanBP 9-Delta 1/N60片段显示出增强的细胞质相对于核定位和比全长RanBP 9增强>3倍的稳定性。重要的是，含有LisH二聚化结构域的RanBP 9-Delta 1/N60保留了形成自相互作用多聚体复合物的能力，并使A β产生增加了载体对照的5倍，比全长RanBP 9所见的3倍增加更有效。总之，这些数据表明RanBP 9-N60可以进一步驱动AD中的淀粉样蛋白级联反应，并且RanBP 9的蛋白水解加工可能是有吸引力的治疗靶点。Lakshmana，M. K.，钟振英，Wickramarachchi，S.，Tak，E.，比安奇，Koo，E. H、康氏D. E.支架蛋白RanBP 9的片段在阿尔茨海默病大脑中增加，并强烈增强淀粉样β肽的产生。FASEB J.24，119 -127（2010）。www.fasebj.org
Increasing biochemical and genetic evidence indicates that the amyloid-beta ( A beta)peptide derived from amyloid precursor protein (APP) plays a central role in Alzheimer's disease ( AD) pathogenesis. We previously reported that RanBP9 promotes A beta generation by scaffolding APP/BACE1/LRP complexes together. Interestingly, the RanBP9-Delta 1/N60 ( residues 1-392) deletion mutant interacted much more strongly with APP/BACE1/LRP than full-length RanBP9. In this study, we found that RanBP9-N60, a processed form of RanBP9 virtually identical to the RanBP9-Delta 1/N60 mutant, was strongly increased in AD brains compared with controls. To evaluate the potential pathogenic consequences of this phenotype, we studied the differential biological properties of full-length RanBP9 vs. RanBP9-Delta 1/N60 in HEK293T and Neuro-2A cells. The RanBP9-Delta 1/N60 fragment, which lacks a nuclear localization signal, displayed enhanced cytoplasmic vs. nuclear localization and >3-fold enhanced stability than full-length RanBP9. Importantly, RanBP9-Delta 1/N60, which contains the LisH dimerization domain, retained the capacity to form self-interacting multimeric complexes and increased A beta generation by similar to 5-fold over vector controls, more potent than the similar to 3-fold increase seen by full-length RanBP9. Taken together, these data indicate that RanBP9-N60 may further drive the amyloid cascade in AD and that the proteolytic processing of RanBP9 may be an attractive therapeutic target.-Lakshmana, M. K., Chung, J. Y., Wickramarachchi, S., Tak, E., Bianchi, E., Koo, E. H., Kang, D. E. A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid beta peptide generation. FASEB J. 24,119-127 ( 2010). www.fasebj.org