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Published on: April 21, 2023
Oxidation resistance 1 regulates post-translational modifications of peroxiredoxin 2 in the cerebellum
Daria M Svistunova1, Jillian N Simon2, Elzbieta Rembeza3
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
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.
Insights
Oxidation resistance 1 (Oxr1) regulates peroxiredoxin 2 (Prdx2) function, acting as a switch between its antioxidant and chaperone roles. This interaction is crucial for preventing neurodegeneration linked to oxidative stress.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Neurodegenerative disorders share common etiological factors like protein aggregation and oxidative stress.
- Oxidation resistance 1 (Oxr1) is neuroprotective, but its mechanisms are not fully understood.
- Peroxiredoxin 2 (Prdx2) is a brain-abundant antioxidant and molecular chaperone.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying Oxr1's neuroprotective effects.
- To investigate the interaction between Oxr1 and Prdx2.
- To determine how Oxr1 influences Prdx2 function in neurodegeneration.
Main Methods:
- In vitro biochemical assays.
- In vivo studies using two distinct animal models.
- Analysis of protein expression, oligomerization, and post-translational modifications (PTMs).
Main Results:
- Oxr1 directly interacts with Prdx2.
- Oxr1 expression levels control Prdx2 oligomerization and PTMs.
- Oxr1 acts as a functional switch for Prdx2's antioxidant and chaperone activities.
- Oxr1 deficiency leads to aberrant Prdx2 modifications and cerebellar neurodegeneration in mice.
Conclusions:
- Oxr1 is a key regulator of Prdx2 function, impacting its roles in cellular defense.
- Dysregulation of the Oxr1-Prdx2 axis contributes to neurodegeneration, particularly in the cerebellum.
- Targeting the Oxr1-Prdx2 interaction may offer novel therapeutic strategies for neurodegenerative diseases.
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