Liang Ziqi, Liu Wanqing, Cao Mian, Cui Jiajun, Lan Jinshuai, Ding Yue, Zhang Tong, Yang Zizhao
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China.
Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore; Department of Physiology, National University of Singapore, Singapore, 169857, Singapore.
Theranostics. 2025 Jan 13;15(6):2250-2278. doi: 10.7150/thno.107436. eCollection 2025.
Mechanisms such as DNA methylation, histone modifications, and non-coding RNA regulation may impact the endocytosis of dopamine transporter (DAT) by influencing processes like neuronal survival, thereby contributing to the initiation and progression of Parkinson's Disease (PD). Some small molecule inhibitors or natural bioactive compounds have the potential to modulate epigenetic processes, thereby reversing induced pluripotent stem cells (iPSCs) reprogramming and abnormal differentiation, offering potential therapeutic effects for PD. Although no specific DNA modification enzyme directly regulates DAT endocytosis, enzymes such as DNA methyltransferases (DNMTs) may indirectly influence DAT endocytosis by regulating the expression of genes associated with this process. DNA modifications impact DAT endocytosis by modulating key signaling pathways, including the (protein kinase C) PKC and D2 receptor (D2R) pathways. Key enzymes involved in RNA modifications that influence DAT endocytosis include mA methyltransferases and other related enzymes. This regulation impacts the synthesis and function of proteins involved in DAT endocytosis, thereby indirectly affecting the process itself. RNA modifications regulate DAT endocytosis through various indirect pathways, as well as histone modifications. Key enzymes influence the expression of genes associated with DAT endocytosis by modulating the chromatin's accessibility and compaction state. These enzymes control the expression of proteins involved in regulating endocytosis, promoting endosome formation, and facilitating recycling processes. Through the modulation exerted by these enzymes, the speed of DAT endocytosis and recycling patterns are indirectly regulated, establishing a crucial epigenetic control point for the regulation of neurotransmitter transport. Based on this understanding, we anticipate that targeting these processes could lead to favorable therapeutic effects for early PD pathogenesis.
DNA甲基化、组蛋白修饰和非编码RNA调控等机制可能通过影响神经元存活等过程来影响多巴胺转运体（DAT）的内吞作用，从而促进帕金森病（PD）的发生和发展。一些小分子抑制剂或天然生物活性化合物有可能调节表观遗传过程，从而逆转诱导多能干细胞（iPSC）的重编程和异常分化，为PD提供潜在的治疗效果。虽然没有特定的DNA修饰酶直接调节DAT内吞作用，但DNA甲基转移酶（DNMT）等酶可能通过调节与此过程相关的基因表达来间接影响DAT内吞作用。DNA修饰通过调节关键信号通路，包括蛋白激酶C（PKC）和D2受体（D2R）通路，来影响DAT内吞作用。参与影响DAT内吞作用的RNA修饰的关键酶包括mA甲基转移酶和其他相关酶。这种调节影响参与DAT内吞作用的蛋白质的合成和功能，从而间接影响该过程本身。RNA修饰通过各种间接途径以及组蛋白修饰来调节DAT内吞作用。关键酶通过调节染色质的可及性和压缩状态来影响与DAT内吞作用相关的基因表达。这些酶控制参与调节内吞作用、促进内体形成和促进再循环过程的蛋白质的表达。通过这些酶施加的调节，间接调节了DAT内吞作用的速度和再循环模式，为神经递质运输的调节建立了一个关键的表观遗传控制点。基于这一认识，我们预计针对这些过程可能会对早期PD发病机制产生良好的治疗效果。
