Striatum-enriched protein, arginase 2 localizes to medium spiny neurons and controls striatal metabolic profile

• Published in: Neurochemistry international 2025-01, Vol.182, p.105907, Article 105907
• Main Authors: Nalepa, Martyna, Toczyłowska, Beata, Owczarek, Aleksandra, Skweres, Aleksandra, Ziemińska, Elżbieta, Węgrzynowicz, Michał
• Format: Article
• Language: English
• Subjects: Arginase 2; Medium spiny neurons; Metabolic profiles; Mitochondria; NMR spectroscopy; Striatum
• ISSN: 0197-0186; 1872-9754; 1872-9754
• DOI: 10.1016/j.neuint.2024.105907

Arginase 2 (Arg2) is the predominant arginase isoenzyme in the brain, however its distribution appears to be limited to selected, region-specific subpopulations of cells. Although striatum is highly enriched with Arg2, precise localization and function of striatal Arg2 have never been studied. Here, we confirm that Arg2 is the only arginase isoenzyme in the striatum, and, using genetic model of total Arg2 loss, we show that Arg2 in this region is fully responsible for arginase catalytic activity, and its loss doesn't induce compensatory activation of Arg1. We exhibit that Arg2 is present in medium spiny neurons (MSNs), striatum-specific projecting neurons, where it localizes in soma and neuronal processes, and is absent in astrocytes or microglia. Finally, analysis of NMR spectroscopy-measured metabolic profiles of striata of Arg2-null mice enabled to recognize two metabolites (NADH and malonic acid) to be significantly altered compared to control animals. Multivariate comparison of the data using orthogonal projections to latent structures discriminant analysis, allowed for discrimination between control and Arg2-null mice and identified metabolites that contributed the most to this between-group dissimilarity. Our study reveals for the first time the localization of Arg2 in MSNs and demonstrates significant role of this enzyme in regulating striatal metabolism. These findings may be especially interesting in the context of Huntington's disease (HD), a disorder that specifically affects MSNs and in which, with the use of mouse models, the onset of pathological phenotypes was recently shown to be preceded by progressive impairment of striatal Arg2, a phenomenon of an unknown significance for disease pathogenesis. [Display omitted] •In mouse striatum, arginase 2 localizes specifically to the medium spiny neurons.•Arginase 2 is solely responsible for striatal arginase catalytic activity.•Arginase 2 loss results in significant alterations in striatal metabolic profiles.•Loss of arginase 2 leads to NADH decrease and malonate increase in the striatum.