Abstract
Mitochondrial dysfunction is a key element in the pathogenesis of neurodegenerative disorders, such as riboflavin transporter deficiency (RTD). This is a rare, childhood-onset disease characterized by motoneuron degeneration and caused by mutations in SLC52A2 and SLC52A3, encoding riboflavin (RF) transporters (RFVT2 and RFVT3, respectively), resulting in muscle weakness, ponto-bulbar paralysis and sensorineural deafness. Based on previous findings, which document the contribution of oxidative stress in RTD pathogenesis, we tested possible beneficial effects of several antioxidants (Vitamin C, Idebenone, Coenzyme Q10 and EPI-743, either alone or in combination with RF) on the morphology and function of neurons derived from induced pluripotent stem cells (iPSCs) from two RTD patients. To identify possible improvement of the neuronal morphotype, neurite length was measured by confocal microscopy after β-III tubulin immunofluorescent staining. Neuronal function was evaluated by determining superoxide anion generation by MitoSOX assay and intracellular calcium (Ca2+) levels, using the Fluo-4 probe. Among the antioxidants tested, EPI-743 restored the redox status, improved neurite length and ameliorated intracellular calcium influx into RTD motoneurons. In conclusion, we suggest that antioxidant supplementation may have a role in RTD treatment.
Highlights
Neurodegenerative diseases (ND), constitute a spectrum of chronic debilitating disorders characterized by irreversible progressive loss of neurons
MitoSOX fluorescence intensity was measured under basal conditions and after antioxidant supplementation to determine the optimal concentration for reduction of O2 − in riboflavin transporter deficiency (RTD) induced pluripotent stem cells (iPSCs)
Incubating RTD iPSCs with BODIPY showed increased levels of green fluorescence, indicating increased levels of oxidized lipids in RTD iPSCs compared to control cells. We used this endophenotype of iPSCs to assess the antioxidant properties of EPI-743 as it is reported to have 15-lipoxygenase as a direct target
Summary
Neurodegenerative diseases (ND), constitute a spectrum of chronic debilitating disorders characterized by irreversible progressive loss of neurons. The brain regions and cell types affected in various neurodegenerative disorders are disease-specific, common factors contribute to their pathogenesis, among which progressive destabilization of microtubules, axonal and dendritic degeneration, energy dysmetabolism and oxidative stress are shared events [1,2]. Leakage of electrons from the electron transport chain generates of reactive oxygen species (ROS), such as hydroxyl radical, superoxide anion and hydrogen peroxide [8]. These species act as signalling molecules, inducing biological responses such as proliferation, migration, and differentiation [9,10], but their overproduction can damage proteins, lipids and nucleic acids, impairing normal metabolism [1,9]. The levels of protective antioxidants in the nervous system are lower than those in other tissues, which further make neurons vulnerable cells [10,11]
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