Walter Natalie Monet, Yde Ohki Cristine Marie, Rickli Michelle, Smigielski Lukasz, Walitza Susanne, Grünblatt Edna
Department of Child and Adolescent Psychiatry and Psychotherapy, Translational Molecular Psychiatry, Psychiatric University Hospital Zurich, University of Zurich, Wagistrasse 12, 8952, Schlieren, Switzerland.
Biomedicine PhD Program, University of Zurich, Winterthurerstrasse 11, 8057, Zurich, Switzerland.
Neurosci Appl. 2024 Apr 20;3:104070. doi: 10.1016/j.nsa.2024.104070. eCollection 2024.
The canonical Wnt signaling pathway plays a vital role in the developmental processes of the Central Nervous System throughout both prenatal and postnatal stages, as well as in maintaining homeostasis during adulthood. Its complex intracellular cascade involves the participation of key proteins (i.e., GSK3β and β-catenin) to activate the transcription of Wnt target genes. These genes subsequently control processes like cell proliferation, maturation, and the determination of cell fate. Previous studies suggest that this pathway can also be associated with Attention-Deficit Hyperactivity Disorder (ADHD), a neurodevelopmental disorder with multifactorial etiology. This study aimed to clarify if and at what developmental stage the Wnt pathway is altered in ADHD. Accordingly, we carried out proteomic and functional assessments of the Wnt pathway using Western Blot and reporter assays, respectively. These assessments were performed at the induced pluripotent stem cell (iPSC), neural stem cell (NSC), and neuronal phases. IPSCs were generated from somatic cells retrieved from 5 controls and 5 patients diagnosed with ADHD. As opposed to the developmental stage of iPSCs, ADHD NSCs showed alterations in the protein expression of both GSK3β and β-catenin, suggesting increased Wnt activity in the ADHD group. Moreover, Wnt reporter assays confirmed higher Wnt activity in ADHD NSCs. Our molecular findings in NSCs correlated with genetic predisposition to ADHD and clinical traits displayed by their respective donors. In conclusion, these results suggest that a crucial cellular pathway is disrupted in patient-specific NSCs, potentially explaining the developmental deficits clinically exhibited by ADHD patients.
经典Wnt信号通路在中枢神经系统产前和产后阶段的发育过程中以及成年期维持体内平衡方面发挥着至关重要的作用。其复杂的细胞内级联反应涉及关键蛋白（即GSK3β和β-连环蛋白）的参与，以激活Wnt靶基因的转录。这些基因随后控制细胞增殖、成熟和细胞命运决定等过程。先前的研究表明，该通路也可能与注意力缺陷多动障碍（ADHD）有关，ADHD是一种病因多因素的神经发育障碍。本研究旨在阐明ADHD中Wnt通路是否以及在什么发育阶段发生改变。因此，我们分别使用蛋白质印迹法和报告基因检测对Wnt通路进行了蛋白质组学和功能评估。这些评估在诱导多能干细胞（iPSC）、神经干细胞（NSC）和神经元阶段进行。iPSC由从5名对照和5名被诊断为ADHD的患者中获取的体细胞生成。与iPSC的发育阶段不同，ADHD神经干细胞在GSK3β和β-连环蛋白的蛋白表达上均显示出改变，这表明ADHD组中Wnt活性增加。此外，Wnt报告基因检测证实ADHD神经干细胞中Wnt活性更高。我们在神经干细胞中的分子发现与ADHD的遗传易感性及其各自供体表现出的临床特征相关。总之，这些结果表明，在患者特异性神经干细胞中一条关键的细胞通路被破坏，这可能解释了ADHD患者临床上表现出的发育缺陷。
