PUBLICATION
Converging Role for REEP1/SPG31 in Oxidative Stress
- Authors
- Naef, V., Meschini, M.C., Tessa, A., Morani, F., Corsinovi, D., Ogi, A., Marchese, M., Ori, M., Santorelli, F.M., Doccini, S.
- ID
- ZDB-PUB-230226-61
- Date
- 2023
- Source
- International Journal of Molecular Sciences 24(4): (Journal)
- Registered Authors
- Ori, Michela
- Keywords
- REEP1, ROS, SPG31, bioenergetic defects, mitochondria, resveratrol, zebrafish
- MeSH Terms
-
- Animals
- Axons/metabolism
- Membrane Transport Proteins*/metabolism
- Mutation
- Oxidative Stress
- Spastic Paraplegia, Hereditary*/genetics
- Zebrafish/metabolism
- PubMed
- 36834939 Full text @ Int. J. Mol. Sci.
Citation
Naef, V., Meschini, M.C., Tessa, A., Morani, F., Corsinovi, D., Ogi, A., Marchese, M., Ori, M., Santorelli, F.M., Doccini, S. (2023) Converging Role for REEP1/SPG31 in Oxidative Stress. International Journal of Molecular Sciences. 24(4):.
Abstract
Mutations in the receptor expression-enhancing protein 1 gene (REEP1) are associated with hereditary spastic paraplegia type 31 (SPG31), a neurological disorder characterized by length-dependent degeneration of upper motor neuron axons. Mitochondrial dysfunctions have been observed in patients harboring pathogenic variants in REEP1, suggesting a key role of bioenergetics in disease-related manifestations. Nevertheless, the regulation of mitochondrial function in SPG31 remains unclear. To elucidate the pathophysiology underlying REEP1 deficiency, we analyzed in vitro the impact of two different mutations on mitochondrial metabolism. Together with mitochondrial morphology abnormalities, loss-of-REEP1 expression highlighted a reduced ATP production with increased susceptibility to oxidative stress. Furthermore, to translate these findings from in vitro to preclinical models, we knocked down REEP1 in zebrafish. Zebrafish larvae showed a significant defect in motor axon outgrowth leading to motor impairment, mitochondrial dysfunction, and reactive oxygen species accumulation. Protective antioxidant agents such as resveratrol rescued free radical overproduction and ameliorated the SPG31 phenotype both in vitro and in vivo. Together, our findings offer new opportunities to counteract neurodegeneration in SPG31.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping