Epigenetic regulation-mediated disorders in dopamine transporter endocytosis: A novel mechanism for the pathogenesis of Parkinson's disease.

Abstract

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 m⁶A 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.