The Critical Role of Post-Translational Modification and Epigenetic Mechanism in Dopamine Neurons

Abstract

Dopamine (DA) is one of the brain's major neurotransmitters, responsible for important functions such as movement and addiction. DA is released from DA neurons located in various regions of the brain, including the hypothalamus, midbrain, and olfactory bulb. As these neurons are a diverse group in terms of anatomical distribution and functional properties, many studies are exploring to elucidate the physiological properties of DA neurons. Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative disorder associated with aging, following Alzheimer's disease. It manifests with symptoms such as tremors, bradykinesia, muscle stiffness, as well as difficulties in walking and maintaining posture. PD is marked by the depletion of DA neurons in the substantia nigra (SNc) and reduced DA levels in the striatum, yet its exact cause remains unknown. Therefore, a thorough comprehension of DA neurons is crucial for advancing our understanding of PD and developing new therapeutic strategies for it. In this dissertation, I introduce and demonstrate two biological mechanisms that are present in DA neurons. In addition, I discuss the importance of each mechanism in DA neurons by proposing their roles in DA neuron survival, functionality, associated behaviors, and the development of PD pathology. In Chapter 3, I explore the role of O-GlcNAcylation in DA neurons. I demonstrate that a deficiency in O-GlcNAcylation within DA neurons leads to significant impairments in their survival and function. My research indicates that these dysfunctions in DA neurons may stem from a reduction in the expression of DA neuron-specific genes. Conversely, increasing O-GlcNAcylation selectively in DA neurons does not produce adverse effects but instead enhances DA release at the axon terminal. This elevation in O-GlcNAc in DA neurons triggers various patterns of protein O-GlcNAcylation, revealing the intricate interplay between O-GlcNAc and proteins in DA neurons. Lastly, I propose that elevating O-GlcNAcylation in DA neurons through genetic or pharmacological methods exerts a neuroprotective effect against PD pathology induced by α-synuclein aggregation. In Chapter 4, I investigate the function of DNA demethylation and TET proteins in DA neurons. My research reveals that the absence of 5hmc in DA neurons due to Tet deletion has minimal impact on the soma of DA neurons but leads to a decrease in DA release and expression of DA release-related proteins at their axon terminals. Consequently, this reduction disrupts basal locomotion and motor learning, highlighting the significance of DNA demethylation in the functions of DA neurons. In Chapter 5, I provide a summary of the significant discoveries presented in this dissertation and outline potential future research directions to advance the field. Overall, my study highlights the importance of two critical biological mechanisms in DA neurons and their relevance to the pathology of PD. Through this dissertation, I aim to provide a new comprehensive understanding of DA neuron physiology via these biologically essential processes. This progress will contribute to the introduction of new therapeutic strategies in the development of treatments for PD.