DYRK1A: A Potential Drug Target for Multiple Down Syndrome Neuropathologies
DYRK1A: A Potential Drug Target for Multiple Down Syndrome Neuropathologies
复制标题
DOI：
10.2174/18715273113126660186
复制
发表时间：
2014-02-01
影响因子：
3
通讯作者：
Tejedor, Francisco J.
中科院分区：
文献类型：
--
作者：
Becker, Walter;Soppa, Ulf;Tejedor, Francisco J.
唐氏综合症（DS）是智力残疾最常见的遗传原因，是由21号染色体三体引起的。MNB/DYRK1A （Minibrain/双特异性酪氨酸磷酸化调节激酶1A）可能是过去十年中研究最广泛的21号染色体基因，因为它在大脑中的功能与重要的退行性痴呆神经病变（如神经元缺陷、树突萎缩、脊柱发育不良、早发性阿尔茨海默氏样神经变性和认知缺陷）具有显著的相关性。MNB/DYRK1A已成为一个有吸引力的药物靶点，因为越来越多的证据表明其过表达可能诱导ds样神经生物学改变，并且有几种小分子抑制剂可以抑制其蛋白激酶活性。在这里，我们从DS-research的角度总结了MNB/DYRK1A的功能复杂性，特别关注不同MNB/DYRK1A抑制剂在实验模型中逆转MNB/DYRK1A活性增加所引起的神经生物学改变的能力。最后，我们讨论了可能基于MNB/DYRK1A的治疗策略的优缺点，这些策略源于MNB/DYRK1A的功能、分子和药理复杂性。
Down syndrome (DS), the most common genetic cause of intellectual disability, is caused by the trisomy of chromosome 21. MNB/DYRK1A (Minibrain/dual specificity tyrosine phosphorylation-regulated kinase 1A) has possibly been the most extensively studied chromosome 21 gene during the last decade due to the remarkable correlation of its functions in the brain with important DS neuropathologies, such as neuronal deficits, dendrite atrophy, spine dysgenesis, precocious Alzheimer's-like neurodegeneration, and cognitive deficits. MNB/DYRK1A has become an attractive drug target because increasing evidence suggests that its overexpression may induce DS-like neurobiological alterations, and several small-molecule inhibitors of its protein kinase activity are available. Here, we summarize the functional complexity of MNB/DYRK1A from a DS-research perspective, paying particular attention to the capacity of different MNB/DYRK1A inhibitors to reverse the neurobiological alterations caused by the increased activity of MNB/DYRK1A in experimental models. Finally, we discuss the advantages and drawbacks of possible MNB/DYRK1A-based therapeutic strategies that result from the functional, molecular, and pharmacological complexity of MNB/DYRK1A.