帕金森蛋白缺陷和过表达大鼠伏隔核的蛋白质组学图谱：深入了解帕金森蛋白在甲基苯丙胺使用障碍中的作用
The Proteomic Landscape of Parkin-Deficient and Parkin-Overexpressing Rat Nucleus Accumbens: An Insight into the Role of Parkin in Methamphetamine Use Disorder.
作者信息
Sharma Akhil, Atasi Tarek, Collin Florine, Wang Weiwei, Lam TuKiet T, Garcia-Milian Rolando, Arroum Tasnim, Pham Lucynda, Hüttemann Maik, Moszczynska Anna
机构信息
Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
出版信息
Biomolecules. 2025 Jul 3;15(7):958. doi: 10.3390/biom15070958.
In recent years, methamphetamine (METH) misuse in the US has been rapidly increasing, and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). We previously determined that ubiquitin-protein ligase parkin is involved in the regulation of METH addictive behaviors in rat models of MUD. Parkin is not yet a "druggable" drug target; therefore, this study aimed to determine which biological processes, pathways, and proteins downstream of parkin are likely drug targets against MUD. Employing young adult Long Evans male rats with parkin deficit or excess in the nucleus accumbens (NAc), label-free proteomics, and molecular biology, we determined that the pathways downstream of parkin that are candidates for regulating METH addictive behaviors in young adult male rats are mitochondrial respiration, oxidative stress, AMPA receptor trafficking, GABAergic neurotransmission, and actin cytoskeleton dynamics.
近年来，美国甲基苯丙胺（METH）滥用现象迅速增加，且尚无美国食品药品监督管理局（FDA）批准的用于治疗甲基苯丙胺使用障碍（MUD）的药物疗法。我们之前已确定泛素蛋白连接酶帕金参与了甲基苯丙胺使用障碍大鼠模型中甲基苯丙胺成瘾行为的调节。帕金尚未成为一个“可成药的”药物靶点；因此，本研究旨在确定帕金下游的哪些生物学过程、信号通路和蛋白质可能是针对甲基苯丙胺使用障碍的药物靶点。利用伏隔核（NAc）中帕金缺乏或过量的年轻成年雄性朗·埃文斯大鼠、无标记蛋白质组学和分子生物学方法，我们确定了在年轻成年雄性大鼠中帕金下游那些可能调节甲基苯丙胺成瘾行为的信号通路，包括线粒体呼吸、氧化应激、AMPA受体转运、γ-氨基丁酸能神经传递以及肌动蛋白细胞骨架动力学。
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