Neurochemistry Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Molecular Neurobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Int J Mol Sci. 2019 Feb 25;20(4):994. doi: 10.3390/ijms20040994.
The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer's disease (AD) caused by APP gene duplications (Dup⁻APP) and in aging Down syndrome individuals. APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5'untranslated region (5'UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD. By contrast, in younger age groups, APP expression is not associated with amyloidosis, instead it acts solely as a neuroprotectant while facilitating cellular ferroportin-dependent iron efflux. We have reported that the environmental metallotoxins Lead (Pb) and manganese (Mn) cause neuronal death by interfering with IRE dependent translation of APP and ferritin. The loss of these iron homeostatic neuroprotectants thereby caused an embargo of iron (Fe) export from neurons as associated with excess unstored intracellular iron and the formation of toxic reactive oxidative species (ROS). We propose that APP 5'UTR directed translation activators can be employed therapeutically to protect neurons exposed to high acute Pb and/or Mn exposure. Certainly, high potency APP translation activators, exemplified by the Food and Drug Administration (FDA) pre-approved M1 muscarinic agonist AF102B and high throughput-screened APP 5'UTR translation activators, are available for drug development to treat acute toxicity caused by Pb/Mn exposure to neurons. We conclude that APP translation activators can be predicted to prevent acute metal toxicity to neurons by a mechanism related to the 5'UTR specific yohimbine which binds and targets the canonical IRE RNA stem loop as an H-ferritin translation activator.
抑制淀粉样前体蛋白 (APP) 翻译的治疗价值提供了减少神经毒性淀粉样形成的可能性，特别是在由 APP 基因重复 (Dup⁻APP) 引起的家族性阿尔茨海默病 (AD) 和衰老唐氏综合征个体中。APP mRNA 翻译抑制剂，如抗胆碱酯酶苯海索，以及高通量筛选的分子，选择性地抑制 APP mRNA 5'非翻译区 (5'UTR) 中独特折叠的铁反应元件 (IRE) 序列，这类药物继续在临床试验中作为 AD 的抗淀粉样治疗药物进行测试。相比之下，在年龄较小的人群中，APP 表达与淀粉样变性无关，相反，它仅作为神经保护剂，同时促进细胞铁蛋白依赖性铁外排。我们已经报道，环境金属毒素铅 (Pb) 和锰 (Mn) 通过干扰 APP 和铁蛋白的 IRE 依赖性翻译而导致神经元死亡。这些铁稳态神经保护剂的丧失导致铁 (Fe) 从神经元中出口受阻，与过量未储存的细胞内铁和有毒的活性氧化物质 (ROS) 的形成有关。我们提出，APP 5'UTR 定向翻译激活剂可以用于治疗暴露于高急性 Pb 和/或 Mn 暴露的神经元。当然，高活性 APP 翻译激活剂，例如食品和药物管理局 (FDA) 预先批准的 M1 毒蕈碱激动剂 AF102B 和高通量筛选的 APP 5'UTR 翻译激活剂，可用于药物开发，以治疗 Pb/Mn 暴露引起的神经元急性毒性。我们得出结论，APP 翻译激活剂可以通过与 5'UTR 特异性育亨宾相关的机制来预测预防神经元的急性金属毒性，育亨宾结合并靶向规范的 IRE RNA 茎环作为 H 铁蛋白翻译激活剂。
