CDKL5 deficiency disorder (CDD) is a rare X-linked neurodevelopmental disorder that is characterised by early-onset seizures, intellectual disability, gross motor impairment, and autistic-like features. CDD is caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene that encodes a serine/threonine kinase with a predominant expression in the brain. Loss of CDKL5 causes neurodevelopmental alterations in vitro and in vivo, including defective dendritic arborisation and spine maturation, which most likely underlie the cognitive defects and autistic features present in humans and mice. Here, we show that treatment with epigallatocathechin-3-gallate (EGCG), the major polyphenol of green tea, can restore defects in dendritic and synaptic development of primary Cdkl5 knockout (KO) neurons. Furthermore, defective synaptic maturation in the hippocampi and cortices of adult Cdkl5-KO mice can be rescued through the intraperitoneal administration of EGCG, which is however not sufficient to normalise behavioural CDKL5-dependent deficits. EGCG is a pleiotropic compound with numerous cellular targets, including the dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) that is selectively inhibited by EGCG. DYRK1A controls dendritic development and spine formation and its deregulation has been implicated in neurodevelopmental and degenerative diseases. Treatment with another DYRK1A inhibitor, harmine, was capable of correcting neuronal CDKL5-dependent defects; moreover, DYRK1A levels were upregulated in primary Cdkl5-KO neurons in concomitance with increased phosphorylation of Tau, a well-accepted DYRK1A substrate. Altogether, our results indicate that DYRK1A deregulation may contribute, at least in part, to the neurodevelopmental alterations caused by CDKL5 deficiency.

中文翻译：

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绿茶多酚表没食子儿茶素-3-没食子酸酯（EGCG）可在体内和体外恢复CDKL5依赖性突触缺陷。

CDKL5缺乏症（CDD）是一种罕见的X连锁神经发育障碍，其特征是早发性癫痫发作，智力残疾，严重运动障碍和自闭症样特征。CDD是由细胞周期蛋白依赖性激酶样5（CDKL5）基因突变引起的，该基因编码在脑中主要表达的丝氨酸/苏氨酸激酶。CDKL5的丧失会导致体内外神经发育改变，包括有缺陷的树突状树突化和脊柱成熟，这很可能是人类和小鼠存在的认知缺陷和自闭症特征的基础。在这里，我们表明，用绿茶的主要多酚表没食子儿茶素-3-没食子酸酯（EGCG）进行的治疗可以恢复初级Cdkl5敲除（KO）神经元的树突和突触发育中的缺陷。此外，可以通过腹膜内给予EGCG来挽救成年Cdkl5-KO小鼠海马和皮层有缺陷的突触成熟，但这不足以使CDKL5依赖的行为缺陷正常化。EGCG是一种具有多种细胞靶标的多效化合物，包括被EGCG选择性抑制的双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）。DYRK1A控制树突的发展和脊柱的形成，其失调已牵涉到神经发育和退行性疾病。用另一种DYRK1A抑制剂harmine处理能够纠正CDKL5依赖性神经元缺陷。此外，在原代Cdkl5-KO神经元中，DYRK1A水平上调，同时伴随着Tau（一种公认的DYRK1A底物）的磷酸化增加。共，