Novel 5' untranslated region directed blockers of iron-regulatory protein-1 dependent amyloid precursor protein translation: implications for down syndrome and Alzheimer's disease.
Novel 5' untranslated region directed blockers of iron-regulatory protein-1 dependent amyloid precursor protein translation: implications for down syndrome and Alzheimer's disease.
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DOI：
10.1371/journal.pone.0065978
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rogers JT
中科院分区：
文献类型：
--
作者：
Bandyopadhyay S;Cahill C;Balleidier A;Huang C;Lahiri DK;Huang X;Rogers JT
我们报道铁流入驱动神经元淀粉样前体蛋白（APP）的翻译表达，其在铁流出中发挥作用。这是通过 APP mRNA 与铁调节蛋白 1 (IRP1) 的阻遏蛋白相互作用进行经典释放，而 IRP2 控制编码铁储存蛋白铁蛋白的 L 和 H 亚基的 mRNA。在这里，我们鉴定了 13 种有效的 APP 翻译阻断剂，它们选择性地作用于 APP mRNA 5' 非翻译区 (UTR) 中独特配置的铁响应元件 (IRE) RNA 茎环。这些药物对相关朊病毒蛋白 (PrP) mRNA 5'UTR 序列的抑制作用降低了 10 倍。蛋白质印迹证实，该系列中的“第九个”小分子在皮摩尔浓度下选择性减少 SH-SY5Y 细胞中神经 APP 的产生，而不影响活力或 α-突触核蛋白和铁蛋白的表达。 APP blocker-9 (JTR-009) 是一种苯并咪唑，与其他耐受性良好的 APP 5'UTR 定向翻译阻断剂（包括 Posiphen）相比，它能更大程度地减少 SH-SY5Y 神经元细胞中有毒 Aβ 的产生，后者已被证明可以限制阿尔茨海默病 (AD) 小鼠模型中的淀粉样蛋白负担。 RNA 结合测定表明，JTR-009 通过阻止 IRP1 与 APP mRNA 中的 IRE 结合，同时维持 IRP1 与 H-铁蛋白 IRE RNA 茎环的相互作用来发挥作用。因此，JTR-009 组成型抑制由 APP 5'UTR 序列驱动的翻译。钙黄绿素染色显示 JTR-009 不会间接改变神经元细胞的铁摄取，表明与 APP 5'UTR 存在直接相互作用。这些研究为开发小分子提供了关键数据，这些小分子可选择性地减少神经 APP 和 Aβ 的产生，其浓度比之前表征的相关翻译阻滞剂低 10 倍。我们的数据证明了一种新的治疗策略，对 21 号染色体上 APP 基因三体性患者具有潜在影响，该基因是一种与唐氏综合症 (DS) 长期相关的表型，也可能导致家族性阿尔茨海默病。
We reported that iron influx drives the translational expression of the neuronal amyloid precursor protein (APP), which has a role in iron efflux. This is via a classic release of repressor interaction of APP mRNA with iron-regulatory protein-1 (IRP1) whereas IRP2 controls the mRNAs encoding the L- and H-subunits of the iron storage protein, ferritin. Here, we identified thirteen potent APP translation blockers that acted selectively towards the uniquely configured iron-responsive element (IRE) RNA stem loop in the 5′ untranslated region (UTR) of APP mRNA. These agents were 10-fold less inhibitory of 5′UTR sequences of the related prion protein (PrP) mRNA. Western blotting confirmed that the ‘ninth’ small molecule in the series selectively reduced neural APP production in SH-SY5Y cells at picomolar concentrations without affecting viability or the expression of α-synuclein and ferritin. APP blocker-9 (JTR-009), a benzimidazole, reduced the production of toxic Aβ in SH-SY5Y neuronal cells to a greater extent than other well tolerated APP 5′UTR-directed translation blockers, including posiphen, that were shown to limit amyloid burden in mouse models of Alzheimer's disease (AD). RNA binding assays demonstrated that JTR-009 operated by preventing IRP1 from binding to the IRE in APP mRNA, while maintaining IRP1 interaction with the H-ferritin IRE RNA stem loop. Thus, JTR-009 constitutively repressed translation driven by APP 5′UTR sequences. Calcein staining showed that JTR-009 did not indirectly change iron uptake in neuronal cells suggesting a direct interaction with the APP 5′UTR. These studies provide key data to develop small molecules that selectively reduce neural APP and Aβ production at 10-fold lower concentrations than related previously characterized translation blockers. Our data evidenced a novel therapeutic strategy of potential impact for people with trisomy of the APP gene on chromosome 21, which is a phenotype long associated with Down syndrome (DS) that can also cause familial Alzheimer's disease.
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影响因子：
64.5
作者：
Duce JA;Tsatsanis A;Cater MA;James SA;Robb E;Wikhe K;Leong SL;Perez K;Johanssen T;Greenough MA;Cho HH;Galatis D;Moir RD;Masters CL;McLean C;Tanzi RE;Cappai R;Barnham KJ;Ciccotosto GD;Rogers JT;Bush AI
通讯作者：
Bush AI
影响因子：
--
作者：
Bandyopadhyay, Sanghamitra;Ni, Jake;Rogers, Jack T.
通讯作者：
Rogers, Jack T.
影响因子：
3.1
作者：
Morse, LJ;Payton, SM;Rogers, JT
通讯作者：
Rogers, JT
影响因子：
3.3
作者：
Granic A;Padmanabhan J;Norden M;Potter H
通讯作者：
Potter H
DOI：
10.1155/2012/142372
发表时间：
2012
期刊：
Parkinson's disease
影响因子：
--
作者：
Mikkilineni S;Cantuti-Castelvetri I;Cahill CM;Balliedier A;Greig NH;Rogers JT
通讯作者：
Rogers JT