Loss of Arginase 2 Disrupts Striatum-Specific Polyamine Homeostasis

Abstract Arginase converts arginine (Arg) to ornithine (Orn), regulating their availability for the metabolic pathways that utilize these amino acids. The roles of arginase isoenzymes, Arg1 and Arg2, vary by cell type, tissue, and physiological state. In the brain, Arg2 is the predominant isoenzyme, particularly enriched in the striatum, where it localizes to a striatum-specific neuronal population - medium spiny neurons (MSNs). While the precise role of Arg2 in MSNs remains unclear, its loss alters the striatal metabolomic profile, highlighting its metabolic significance. Here, to investigate the basis of these complex metabolic changes, we examined Arg metabolism in Arg2 knockout (Arg2-/-) mice. Targeted analysis of Arg-related metabolites and selected proteins regulating Arg metabolic pathways revealed that Arg2 loss significantly increased Arg levels but did not affect Orn, likely due to compensatory synthesis of Orn from Arg (via arginine:glycine amidinotransferase) and/or proline (via ornithine aminotransferase). Additionally, markers of nitric oxide (NO) production remained unchanged, suggesting that striatal Arg2 is not involved in the regulation of this pathway, a role commonly attributed to arginase. Most notably, Arg2 loss disrupted polyamine homeostasis, shifting the balance toward higher polyamines at the expense of lower ones and altering the expression of polyamine-regulating proteins. These findings highlight Arg2 crucial role in striatal metabolism and its potential relevance to striatum-related disorders. Given that striatal Arg2 impairment has been reported in Huntington’s disease, a neurodegenerative disorder specifically affecting MSNs, understanding its function may provide insights into the pathology. Competing Interest Statement The authors have declared no competing interest. Footnotes Abbreviations: AGAT – arginine:glycine amidinotransferase; Arg – arginine; Arg1 – arginase 1; Arg2 – arginase 2; AZIN – antizyme inhibitor; Cit – Citrulline; GA – guanidinoacetate; Glu – glutamate; Gly – glycine; HD – Huntington’s disease; HPLC – High-Performance Liquid Chromatography; iNOS – inducible nitric oxide synthase; LC-MS – Liquid Chromatography-Mass Spectrometry; MSNs – medium spiny neurons; N1-AcSpm – N1-acetylspermine; N1-AcSpmd – N1-acetylspermidine; NMR – Nuclear Magnetic Resonance; NO – nitric oxide; NOx – nitrates (NO₃⁻) and nitrites (NO₂⁻); OAT – ornithine aminotransferase; OAZ – ornithine decarboxylase antizyme; ODC – ornithine decarboxylase; Orn – ornithine; P5C – 1-Pyrroline-5-carboxylic acid; Pro – proline; Put – putrescine; SMS – spermine synthase; Spm – spermine; Spmd – spermidine; SRM – spermidine synthase