Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice
Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice
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DOI：
10.1073/pnas.1704143114
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发表时间：
2017-09-19
影响因子：
11.1
通讯作者：
Hagiwara, Masatoshi
中科院分区：
文献类型：
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作者：
Nakano-Kobayashi, Akiko;Awaya, Tomonari;Hagiwara, Masatoshi
由 21 号染色体三体引起的唐氏综合症 (DS) 是智力障碍最常见的遗传原因。尽管 DS 的产前诊断已变得可行，但尚无可用于挽救 DS 相关神经认知障碍的治疗方法。我们在神经干细胞 (NSC) 筛选中新发现的一种生长诱导剂对双特异性酪氨酸磷酸化调节激酶 1A (DYRK1A) 具有有效的抑制活性，并且被发现可以挽救 Ts65Dn 衍生的神经球和 DS 患者衍生的人类 NSC 的增殖缺陷。口服这种名为 ALGERNON（改变神经元生成）的化合物可以恢复 DS 小鼠模型中 NSC 的增殖，并增加新生神经元的数量。此外，对怀孕母鼠施用 ALGERNON 可以挽救 DS 小鼠胚胎中异常的皮质形成，并防止 DS 后代出现异常行为。这些数据表明，ALGERNON 产前治疗可以预防 DS 的神经源性表型。
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.