Converging Role for REEP1/SPG31 in Oxidative Stress.
Valentina NaefMaria C MeschiniAlessandra TessaFederica MoraniDebora CorsinoviAsahi OgiMaria MarcheseMichela OriFilippo M SantorelliStefano DocciniPublished in: International journal of molecular sciences (2023)
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.
Keyphrases
- oxidative stress
- reactive oxygen species
- dna damage
- diabetic rats
- ischemia reperfusion injury
- end stage renal disease
- induced apoptosis
- copy number
- poor prognosis
- newly diagnosed
- ejection fraction
- binding protein
- chronic kidney disease
- peritoneal dialysis
- stem cells
- gene expression
- cell therapy
- genome wide
- heat shock
- zika virus
- mesenchymal stem cells
- long non coding rna
- subarachnoid hemorrhage
- endoplasmic reticulum stress
- cerebral ischemia
- patient reported
- blood brain barrier
- drosophila melanogaster