(Francisco J. Tejedor) Instituto de Neurociencias CSIC-UMH, Universidad Miguel Hernandez-Campus de San Juan, 03550 San Juan (Alicante), Spain.
CNS Neurol Disord Drug Targets. 2014 Feb;13(1):26-33. doi: 10.2174/18715273113126660186.
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.
唐氏综合征（DS）是最常见的智力障碍遗传原因，由 21 号染色体三体引起。在过去十年中，由于其在大脑中的功能与重要的 DS 神经病理学之间存在显著相关性，例如神经元缺陷、树突萎缩、脊柱发育不良、早发性阿尔茨海默病样神经退行性变和认知缺陷，MNB/DYRK1A（小脑/双特异性酪氨酸磷酸化调节激酶 1A）可能是研究最广泛的 21 号染色体基因。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，并且已经有几种其蛋白激酶活性的小分子抑制剂可用。在这里，我们从 DS 研究的角度总结了 MNB/DYRK1A 的功能复杂性，特别关注不同的 MNB/DYRK1A 抑制剂逆转实验模型中 MNB/DYRK1A 活性增加引起的神经生物学改变的能力。最后，我们讨论了 MNB/DYRK1A 基于治疗策略的优缺点，这是由 MNB/DYRK1A 的功能、分子和药理学复杂性产生的。
