Objective: To investigate the effects of arginase 2 (Arg2) loss on the striatal mitochondria.

Background: Arginase plays a role in the production of various metabolites involved in major cellular pathways. We recently identified Arg2 as the major cerebral arginase isoenzyme, highly enriched in the striatum, where it is specifically expressed in medium spiny neurons (MSNs), suggesting a potential role in movement control [1]. Notably, striatal Arg2 loss has been observed to precede pathological changes in Huntington’s disease (HD) mouse models, implying a possible involvement of this enzyme in HD pathogenesis [2]. Given that Arg2 is primarily a mitochondrial protein and considering the crucial role of mitochondria in striatal neurodegeneration in HD, we investigated how the deficiency of this enzyme affects striatal mitochondria.

Method: We used the Arg2^-/- mouse line (Arg2tm1Weo/J) as the primary model in this study. Striatal proteomes of Arg2^-/- and Arg2^+/+ mice were analyzed with LC-MS, followed by functional assessment using STRING and GO. Mitochondrial ultrastructure was assessed by electron microscopy (EM), while mitochondrial oxidative metabolism rate was evaluated through in vivo delivery of dihydroethidium, followed by ex vivo fluorescence intensity measurements with the IVIS Spectrum imaging system. The number of MSNs in the striata of Arg2^-/- and Arg2^+/+ mice was estimated using unbiased stereological counting with StereoInvestigator.

Results: GO analysis identified “mitochondria” and “oxidative phosphorylation” among the most represented terms in Arg2^-/- striata, when STRING analysis revealed an interaction network of several components of respiratory complexes. EM study showed ultrastructural changes in neuronal mitochondria in Arg2^-/- striata including increased numbers of blurred, swollen and cristae-depleted mitochondria. Stereological counting, however, revealed no significant difference in the number of MSNs between Arg2^+/+ and Arg2^-/- striata.

Conclusion: Our results highlight the importance of Arg2 for striatal mitochondria. Loss of this protein affects mitochondrial integrity and functioning, which may compromise neuronal health. Given that MSNs are particularly enriched with Arg2, early impairment of this enzyme in HD may render these cells more vulnerable to other pathological effects of mutant Htt toxicity, thereby contributing to the selective sensitivity of MSNs in this disease.

References: 1 Nalepa, M., Toczyłowska, B., Owczarek, A., Skweres, A., Ziemińska, E., & Węgrzynowicz, M. (2025). Striatum-enriched protein, arginase 2 localizes to medium spiny neurons and controls striatal metabolic profile. Neurochemistry international, 182, 105907. https://doi.org/10.1016/j.neuint.2024.105907

2 Bichell, T. J. V., Wegrzynowicz, M., Tipps, K. G., Bradley, E. M., Uhouse, M. A., Bryan, M., Horning, K., Fisher, N., Dudek, K., Halbesma, T., Umashanker, P., Stubbs, A. D., Holt, H. K., Kwakye, G. F., Tidball, A. M., Colbran, R. J., Aschner, M., Neely, M. D., Di Pardo, A., Maglione, V., … Bowman, A. B. (2017). Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington’s disease mouse model. Biochimica et biophysica acta. Molecular basis of disease, 1863(6), 1596–1604. https://doi.org/10.1016/j.bbadis.2017.02.013

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MDS Abstracts - https://www.mdsabstracts.org/abstract/arginase2-a-potential-mediator-in-the-pathology-of-the-stratum/