Oxidation Resistance 1 Modulates Glycolytic Pathways in the Cerebellum via an Interaction with Glucose-6-Phosphate Isomerase

Finelli, Matt�a J.; Paramo, Teresa; Pires, Elisabete; Ryan, Brent J.; Wade-Martins, Richard; Biggin, Philip C.; McCullagh, James; Oliver, Peter L.

Abstract

Glucose metabolism is essential for the brain: it not only provides the required energy for cellular function and communication but also participates in balancing the levels of oxidative stress in neurons. Defects in glucose metabolism have been described in neurodegenerative disease; however, it remains unclear how this fundamental process contributes to neuronal cell death in these disorders. Here, we investigated the molecular mechanisms driving the selective neurodegeneration in an ataxic mouse model lacking oxidation resistance 1 (Oxr1) and discovered an unexpected function for this protein as a regulator of the glycolytic enzyme, glucose-6-phosphate isomerase (GPI/Gpi1). Initially, we present a dysregulation of metabolites of glucose metabolism at the pre-symptomatic stage in the Oxr1 knockout cerebellum. We then demonstrate that Oxr1 and Gpi1 physically and functionally interact and that the level of Gpi1 oligomerisation is disrupted when Oxr1 is deleted in vivo. Furthermore, we show that Oxr1 modulates the additional and less well-understood roles of Gpi1 as a cytokine and neuroprotective factor. Overall, our data identify a new molecular function for Oxr1, establishing this protein as important player in neuronal survival, regulating both oxidative stress and glucose metabolism in the brain.

Citation

Finelli, M. J., Paramo, T., Pires, E., Ryan, B. J., Wade-Martins, R., Biggin, P. C., McCullagh, J., & Oliver, P. L. (2019). Oxidation Resistance 1 Modulates Glycolytic Pathways in the Cerebellum via an Interaction with Glucose-6-Phosphate Isomerase. Molecular Neurobiology, 56(3), 1558-1577. https://doi.org/10.1007/s12035-018-1174-x

• Journal Article Type: Article
• Acceptance Date: Jun 15, 2018
• Online Publication Date: Jun 15, 2018
• Publication Date: 2019-03
• Deposit Date: Jul 25, 2021
• Publicly Available Date: Jul 27, 2021
• Journal: Molecular Neurobiology
• Print ISSN: 0893-7648
• Electronic ISSN: 1559-1182
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 56
• Issue: 3
• Pages: 1558-1577
• DOI: https://doi.org/10.1007/s12035-018-1174-x
• Keywords: Neuroscience (miscellaneous); Cellular and Molecular Neuroscience; Neurology
• Public URL: https://nottingham-repository.worktribe.com/output/5832582
• Publisher URL: https://link.springer.com/article/10.1007%2Fs12035-018-1174-x
• Additional Information: Received: 8 February 2018; Accepted: 1 June 2018; First Online: 15 June 2018