Oxidation resistance 1 regulates post-translational modifications of peroxiredoxin 2 in the cerebellum

Svistunova, Daria M.; Simon, Jillian N.; Rembeza, Elzbieta; Crabtree, Mark; Yue, Wyatt W.; Oliver, Peter L.; Finelli, Matt�a J.

Abstract

Protein aggregation, oxidative and nitrosative stress are etiological factors common to all major neurodegenerative disorders. Therefore, identifying proteins that function at the crossroads of these essential pathways may provide novel targets for therapy. Oxidation resistance 1 (Oxr1) is a protein proven to be neuroprotective against oxidative stress, although the molecular mechanisms involved remain unclear. Here, we demonstrate that Oxr1 interacts with the multifunctional protein, peroxiredoxin 2 (Prdx2), a potent antioxidant enzyme highly expressed in the brain that can also act as a molecular chaperone. Using a combination of in vitro assays and two animal models, we discovered that expression levels of Oxr1 regulate the degree of oligomerization of Prdx2 and also its post-translational modifications (PTMs), specifically suggesting that Oxr1 acts as a functional switch between the antioxidant and chaperone functions of Prdx2. Furthermore, we showed in the Oxr1 knockout mouse that Prdx2 is aberrantly modified by overoxidation and S-nitrosylation in the cerebellum at the presymptomatic stage; this in-turn affected the oligomerization of Prdx2, potentially impeding its normal functions and contributing to the specific cerebellar neurodegeneration in this mouse model.

Citation

Svistunova, D. M., Simon, J. N., Rembeza, E., Crabtree, M., Yue, W. W., Oliver, P. L., & Finelli, M. J. (2019). Oxidation resistance 1 regulates post-translational modifications of peroxiredoxin 2 in the cerebellum. Free Radical Biology and Medicine, 130, 151-162. https://doi.org/10.1016/j.freeradbiomed.2018.10.447

• Journal Article Type: Article
• Acceptance Date: Oct 29, 2018
• Online Publication Date: Oct 31, 2018
• Publication Date: 2019-01
• Deposit Date: Jul 25, 2021
• Publicly Available Date: Jul 26, 2021
• Journal: Free Radical Biology and Medicine
• Print ISSN: 0891-5849
• Electronic ISSN: 1873-4596
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 130
• Pages: 151-162
• DOI: https://doi.org/10.1016/j.freeradbiomed.2018.10.447
• Keywords: Physiology (medical); Biochemistry
• Public URL: https://nottingham-repository.worktribe.com/output/5832563
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0891584918312711?via%3Dihub