Contribution of polymorphic variation of inositol hexakisphosphate kinase 3 (IP6K3) gene promoter to the susceptibility to late onset Alzheimer's disease
Contribution of polymorphic variation of inositol hexakisphosphate kinase 3 (IP6K3) gene promoter to the susceptibility to late onset Alzheimer's disease
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DOI：
10.1016/j.bbadis.2016.06.014
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发表时间：
2016-09-01
影响因子：
6.2
通讯作者：
Rose, Giuseppina
中科院分区：
文献类型：
--
作者：
Crocco, Paolina;Saiardi, Adolfo;Rose, Giuseppina
维持电位和突触传递是神经元代谢必须不断满足的能量要求任务。不能满足这些能量需求会导致神经退行性疾病的发展，包括阿尔茨海默病。阿尔茨海默病的一个突出特征实际上是神经元葡萄糖代谢低下。因此，了解能量代谢的精细控制可能有助于了解神经退行性疾病。最近的研究表明，一类新的信号分子，肌醇焦磷酸，作为能量传感器。它们能够改变线粒体氧化磷酸化和糖酵解通量之间的平衡，最终影响ATP的细胞水平。神经元肌醇焦磷酸合成依赖于神经元富集的肌醇六磷酸激酶3（IP6K3）酶的活性。为了验证肌醇焦磷酸信号传导参与神经退行性疾病，我们对家族性和散发性迟发性阿尔茨海默病（LOAD）患者的11，610基因进行了标记单核苷酸多态性（SNP）分析。发现IP6K3基因5 '侧翼启动子区的两个SNP5与散发性LOAD相关。通过荧光素酶测定表征两个多态性的功能揭示了其中一个（rs28607030）影响IP6K3启动子活性，其中G等位基因显示出增加的活性。由于相同的等位基因对疾病风险具有有益作用，这可能与IP6K3表达的上调有关，从而增加肌醇焦磷酸合成。总之，我们提供了第一个证据的IP6K3基因的遗传变异的LOAD发病机制的贡献。(C)© 2016 Elsevier B.V.版权所有。
Maintenance of electric potential and synaptic transmission are energetically demanding tasks that neuronal metabolism must continually satisfy. Inability to fulfil these energy requirements leads to the development of neurodegenerative disorders, including Alzheimer's disease. A prominent feature of Alzheimer's disease is in fact neuronal glucose hypometabolism. Thus understanding the fine control of energetic metabolism might help to understand neurodegenerative disorders. Recent research has indicated that a novel class of signalling molecules, the inositol pyrophosphates, act as energy sensors. They are able to alter the balance between mitochondrial oxidative phosphorylation and glycolytic flux, ultimately affecting the cellular level of ATP. The neuronal inositol pyrophosphate synthesis relies on the activity of the neuron enriched inositol hexakisphosphate kinase 3 (IP6K3) enzyme. To verify an involvement of inositol pyrophosphate signalling in neurodegenerative disorders, we performed tagging single nucleotide polymorphism (SNP) analysis of the 11,610 gene in patients with familial and sporadic late onset Alzheimer's disease (LOAD). Two SNP5 in the 5'-flanking promoter region of the IP6K3 gene were found to be associated with sporadic LOAD. Characterizing the functionality of the two polymorphisms by luciferase assay revealed that one of them (rs28607030) affects IP6K3 promoter activity, with the G allele showing an increased activity. As the same allele has a beneficial effect on disease risk, this may be related to up regulation of IP6K3 expression, with a consequent increase in inositol pyrophosphate synthesis. In conclusion, we provide the first evidence for a contribution of genetic variability in the IP6K3 gene to LOAD pathogenesis. (C) 2016 Elsevier B.V. All rights reserved.