Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA; Department of Chemical Sciences, Faculty of Applied Sciences, South Eastern University of Sri Lanka, Oluvil, Sri Lanka.
Mol Ther. 2022 Feb 2;30(2):831-844. doi: 10.1016/j.ymthe.2021.05.013. Epub 2021 May 14.
Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the catecholamine (CA) biosynthesis pathway, making TH a molecular target for controlling CA production, specifically dopamine. Dysregulation of dopamine is correlated with neurological diseases such as Parkinson's disease (PD) and post-traumatic stress disorder (PTSD), among others. Previously, we showed that a 49-nucleotide guanine (G)-rich sequence within the human TH promoter adopts two different sets of G-quadruplex (GQ) structures (5'GQ and 3'GQ), where the 5'GQ uses G-stretches I, II, IV, and VI in TH49, which enhances TH transcription, while the 3'GQ utilizes G-stretches II, IV, VI, and VII, which represses transcription. Herein, we demonstrated targeted switching of these GQs to their active state using rationally designed DNA GQ Clips (5'GQ and 3'GQ Clips) to modulate endogenous TH gene expression and dopamine production. As a translational approach, we synthesized a targeted nanoparticle delivery system to effectively deliver the 5'GQ Clip in vivo. We believe this strategy could potentially be an improved approach for controlling dopamine production in a multitude of neurological disorders, including PD.
酪氨酸羟化酶（TH）催化儿茶酚胺（CA）生物合成途径中的限速步骤，使 TH 成为控制 CA 产生的分子靶点，特别是多巴胺。多巴胺的失调与帕金森病（PD）和创伤后应激障碍（PTSD）等神经疾病有关。先前，我们表明人类 TH 启动子内的 49 个核苷酸鸟嘌呤（G）富含序列采用两种不同的 G-四链体（GQ）结构（5'GQ 和 3'GQ），其中 5'GQ 使用 TH49 中的 G 链 I、II、IV 和 VI，增强 TH 转录，而 3'GQ 利用 G 链 II、IV、VI 和 VII，抑制转录。在此，我们使用合理设计的 DNA GQ 夹（5'GQ 和 3'GQ 夹）证明了这些 GQ 向其活性状态的靶向转换，以调节内源性 TH 基因表达和多巴胺产生。作为一种转化方法，我们合成了一种靶向纳米颗粒递送系统，以有效递送至体内的 5'GQ 夹。我们相信，这种策略可能是控制包括 PD 在内的多种神经疾病中多巴胺产生的一种改进方法。
