Department of Pediatrics, University of Colorado Denver, Denver, CO, USA.
Prog Brain Res. 2012;197:73-100. doi: 10.1016/B978-0-444-54299-1.00005-4.
Major efforts in Down syndrome (DS) research have been directed at the identification and functional characterization of genes encoded by human chromosome 21 (HSA21). In parallel with this, tissue samples and cell lines derived from individuals with DS have been examined for abnormalities in gene expression and cellular morphology, and mouse models of DS have been characterized for abnormalities at the molecular, cellular, electrophysiological, and behavioral level. One goal of such investigations has been the identification of effective targets for pharmacotherapies that can prevent or correct the abnormalities and, by extension to human clinical trials, prevent or lessen aspects of the cognitive deficits seen in people with DS. Because it is caused by an extra copy of an entire chromosome, DS has been considered by some as too complicated a genetic perturbation to be amenable to postnatal pharmacological interventions. However, recent data from experiments with one mouse model, the Ts65Dn, have clearly demonstrated that several pharmacological interventions can indeed rescue DS-relevant learning and memory deficits. Extension of mouse data to successful human clinical trials will be aided by understanding the molecular basis of successful drug treatments, that is, how increased expression of HSA21 genes perturbs molecular mechanisms that are targeted and rescued by specific drugs. Here, we review information on HSA21 genes, their expression and their likely contributions to the DS phenotype. We then describe results of a bioinformatics effort that integrates information on genes known to cause intellectual disability when mutated, the pathways in which these genes function, and how these pathways are impacted by HSA21 encoded proteins. This pathway approach to the molecular basis of ID in DS aids in understanding why some drug therapies have been successful in the Ts65Dn and in predicting whether these same drugs are likely to be successful in treating ID in DS. These data can be used to design new experiments and interpret information for prediction of additional targets for effective drug treatments.
唐氏综合征（DS）的研究主要集中在鉴定和功能表征人类 21 号染色体（HSA21）编码的基因上。与此同时，来自 DS 个体的组织样本和细胞系被检查基因表达和细胞形态的异常，并且 DS 的小鼠模型在分子、细胞、电生理和行为水平上的异常特征。这些研究的一个目标是鉴定有效的药物治疗靶点，这些靶点可以预防或纠正异常，并通过扩展到人类临床试验，预防或减轻 DS 患者认知缺陷的某些方面。由于它是由整个染色体的额外拷贝引起的，因此一些人认为 DS 是一种过于复杂的遗传扰动，无法进行产后药物干预。然而，来自一个小鼠模型 Ts65Dn 的实验的最新数据清楚地表明，几种药物干预确实可以挽救 DS 相关的学习和记忆缺陷。将小鼠数据扩展到成功的人类临床试验将有助于了解成功药物治疗的分子基础，即 HSA21 基因的表达增加如何扰乱特定药物靶向和挽救的分子机制。在这里，我们回顾了 HSA21 基因的信息、它们的表达及其对 DS 表型的可能贡献。然后，我们描述了一个生物信息学研究的结果，该研究整合了已知在突变时导致智力障碍的基因的信息、这些基因在其中发挥作用的途径，以及这些途径如何受到 HSA21 编码蛋白的影响。这种针对 DS 中 ID 的分子基础的途径方法有助于理解为什么一些药物治疗在 Ts65Dn 中是成功的，并预测这些相同的药物是否有可能成功治疗 DS 中的 ID。这些数据可用于设计新的实验并解释信息，以预测有效的药物治疗的其他靶点。
