Chauhan Heli, Carruthers Nicholas J, Stemmer Paul M, Schneider Bernard L, Moszczynska Anna
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA.
Institute of Environmental Health Sciences and Proteomics Core Facility, 540 East Canfield Ave., Detroit, MI 48202, USA.
Int J Mol Sci. 2024 Dec 5;25(23):13070. doi: 10.3390/ijms252313070.
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). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including the dysfunction of the neuroprotective protein parkin. However, it is not known whether parkin loss of function within striatal dopaminergic (DAergic) terminals translates into decreased DA storage capacity. This study examined the relationship between parkin, its substrate cell division cycle related-1 (CDCrel-1) associated with synaptic vesicles, and vesicular monoamine transporter-2 (VMAT2) responsible for packaging DA in an in vivo model of METH neurotoxicity. To assess the individual differences in response to METH's neurotoxic effects, a large group of male Sprague Dawley rats were treated with binge METH or saline and sacrificed 1 h or 24 h later. This study is the first to show that CDCrel-1 interacts with VMAT2 in the rat striatum and that binge METH can alter this interaction as well as the levels and subcellular localization of CDCrel-1. The proteomic analysis of VMAT-2-associated proteins revealed the upregulation of several proteins involved in the exocytosis/endocytosis cycle and responses to stress. The results suggest that DAergic neurons are engaged in counteracting METH-induced toxic effects, including attempts to increase endocytosis and autophagy at 1 h after the METH binge, with the responses varying widely between individual rats. Studying CDCrel-1, VMAT2, and other proteins in large groups of outbred rats can help define individual genetic and molecular differences in responses to METH neurotoxicity, which, in turn, may aid treating humans suffering from MUD and its neurological consequences.
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。除了对药物产生依赖外，患有MUD的人还会出现与该药物毒性相关的各种神经问题。已确定了多种METH神经毒性的分子机制，包括神经保护蛋白帕金（parkin）功能障碍。然而，尚不清楚纹状体多巴胺能（DAergic）终末内帕金功能丧失是否会导致多巴胺储存能力下降。本研究在METH神经毒性的体内模型中，研究了帕金、其与突触小泡相关的底物细胞分裂周期相关蛋白1（CDCrel-1）以及负责包装多巴胺的囊泡单胺转运体2（VMAT2）之间的关系。为了评估对METH神经毒性作用反应的个体差异，一大群雄性斯普拉格-道利大鼠接受了大剂量METH或生理盐水治疗，并在1小时或24小时后处死。本研究首次表明，CDCrel-1在大鼠纹状体中与VMAT2相互作用，且大剂量METH可改变这种相互作用以及CDCrel-1的水平和亚细胞定位。对VMAT-2相关蛋白的蛋白质组学分析揭示了几种参与胞吐作用/胞吞作用循环和应激反应的蛋白上调。结果表明，多巴胺能神经元参与对抗METH诱导的毒性作用，包括在大剂量METH给药后1小时试图增加胞吞作用和自噬作用，且个体大鼠之间的反应差异很大。在大量远交系大鼠中研究CDCrel-1、VMAT2和其他蛋白有助于确定对METH神经毒性反应的个体遗传和分子差异，这反过来可能有助于治疗患有MUD及其神经后果的人类患者。
