Cavarischia-Rega Claudia, Sharma Karan, Fitzgerald Julia C, Macek Boris
Department of Biology, Quantitative Proteomics, University of Tübingen, Tübingen, Germany.
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Front Mol Neurosci. 2025 Jul 30;18:1642519. doi: 10.3389/fnmol.2025.1642519. eCollection 2025.
Dopaminergic neurons, primarily located in the substantia nigra, hypothalamus, and ventral tegmental area of the brain, play crucial roles in motor control, reward, motivation, and cognition. Alterations in their function are associated with numerous neurological and psychiatric disorders, such as Parkinson's disease, but also Schizophrenia, substance use disorders, and bipolar disorder. Recent advances in mass spectrometry-based proteomics have enabled the comprehensive profiling of protein expression, turnover, subcellular localization, and post-translational modifications at an unprecedented depth of analysis. This review summarizes the developments in proteomic approaches taken to study dopaminergic neurons. We cover findings from global and spatial proteomics studies that revealed brain region-specific protein signatures, as well as dynamic turnover of proteins and the importance of mitochondrial and synaptic proteins for the health and vulnerability of dopaminergic neurons. Combined with advanced molecular cell biology tools, such as growth in microfluidic devices, fluorescent-activated synaptosome sorting, and enzymatic proximity labeling, modern proteomics allows for investigation of synaptic and subcellular proteomes. Despite these advancements, the complexity of the human brain and its cell-specific characteristics remain a challenge. The continuing integration of advanced proteomic techniques with other -omics will eventually yield improved and mechanistic understanding of dopaminergic neurons in health and disease.
多巴胺能神经元主要位于大脑的黑质、下丘脑和腹侧被盖区，在运动控制、奖赏、动机和认知中发挥着关键作用。其功能改变与多种神经和精神疾病相关，如帕金森病，还有精神分裂症、物质使用障碍和双相情感障碍。基于质谱的蛋白质组学的最新进展使得能够以前所未有的深度分析对蛋白质表达、周转、亚细胞定位和翻译后修饰进行全面的分析。本综述总结了用于研究多巴胺能神经元的蛋白质组学方法的进展。我们涵盖了来自全局和空间蛋白质组学研究的发现，这些研究揭示了脑区特异性蛋白质特征，以及蛋白质的动态周转，以及线粒体和突触蛋白对多巴胺能神经元健康和易损性的重要性。结合先进的分子细胞生物学工具，如微流控装置中的生长、荧光激活突触体分选和酶促邻近标记，现代蛋白质组学能够研究突触和亚细胞蛋白质组。尽管有这些进展，但人类大脑的复杂性及其细胞特异性特征仍然是一个挑战。先进的蛋白质组学技术与其他“组学”的持续整合最终将提高对健康和疾病状态下多巴胺能神经元的理解，并揭示其机制。
