Converging Role for REEP1/SPG31 in Oxidative Stress

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.

Automated summary

Mutations in the REEP1 gene are associated with SPG31, which is characterized by degeneration of upper motor neuron axons. Mitochondrial dysfunctions have been observed in SPG31 patients, suggesting a role of bioenergetics in the disease. Through in vitro and zebrafish experiments, the study found that loss of REEP1 expression led to mitochondrial abnormalities, reduced ATP production, increased susceptibility to oxidative stress, motor impairment, and reactive oxygen species accumulation. Treatment with the antioxidant resveratrol showed potential in ameliorating SPG31 symptoms. These findings provide new insights for the treatment of SPG31.