Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10268-10273. doi: 10.1073/pnas.1704143114. Epub 2017 Sep 5.
Down syndrome (DS) caused by trisomy of chromosome 21 is the most common genetic cause of intellectual disability. Although the prenatal diagnosis of DS has become feasible, there are no therapies available for the rescue of DS-related neurocognitive impairment. A growth inducer newly identified in our screen of neural stem cells (NSCs) has potent inhibitory activity against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and was found to rescue proliferative deficits in Ts65Dn-derived neurospheres and human NSCs derived from individuals with DS. The oral administration of this compound, named ALGERNON (altered generation of neurons), restored NSC proliferation in murine models of DS and increased the number of newborn neurons. Moreover, administration of ALGERNON to pregnant dams rescued aberrant cortical formation in DS mouse embryos and prevented the development of abnormal behaviors in DS offspring. These data suggest that the neurogenic phenotype of DS can be prevented by ALGERNON prenatal therapy.
唐氏综合征（DS）由 21 号染色体三体引起，是智力障碍最常见的遗传原因。尽管对 DS 的产前诊断已成为可能，但尚无针对 DS 相关神经认知障碍的治疗方法。我们在神经干细胞（NSC）的筛选中发现了一种新的生长诱导剂，它对双特异性酪氨酸磷酸化调节激酶 1A（DYRK1A）具有强烈的抑制活性，并且被发现可挽救 Ts65Dn 衍生的神经球和源自 DS 患者的人 NSCs 的增殖缺陷。该化合物的口服制剂名为 ALGERNON（神经元的改变生成），可恢复 DS 小鼠模型中的 NSC 增殖，并增加新生神经元的数量。此外，向妊娠母鼠施用 ALGERNON 可挽救 DS 小鼠胚胎中皮质形成的异常，并防止 DS 后代出现异常行为。这些数据表明，ALGERNON 产前治疗可预防 DS 的神经发生表型。
