Antioxidant Amelioration of Riboflavin Transporter Deficiency in Motoneurons Derived from Patient-Specific Induced Pluripotent Stem Cells

• Published in: International journal of molecular sciences 2020-10, Vol.21 (19), p.7402
• Main Authors: Marioli, Chiara, Magliocca, Valentina, Petrini, Stefania, Niceforo, Alessia, Borghi, Rossella, Petrillo, Sara, La Rosa, Piergiorgio, Colasuonno, Fiorella, Persichini, Tiziana, Piemonte, Fiorella, Massey, Keith, Tartaglia, Marco, Moreno, Sandra, Bertini, Enrico, Compagnucci, Claudia
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animals; Antioxidants; Antioxidants - pharmacology; Ascorbic acid; Ataxia; Biomarkers; Bulbar Palsy, Progressive; Calcium (intracellular); Calcium - metabolism; Calcium influx; Calcium ions; Cell cycle; Cell Differentiation; Children; Coenzyme Q10; Confocal microscopy; Cytology; Deafness; Degeneration; Disease Models, Animal; Enzymes; Health aspects; Hearing Loss, Sensorineural; Homeostasis; Humans; Induced Pluripotent Stem Cells - cytology; Inhibitory postsynaptic potentials; Intracellular; Lipid Metabolism; Lipid peroxidation; Lipids; Membrane Transport Proteins - deficiency; Mice; Mice, Knockout; Mitochondria; Morphology; Motor neurons; Motor Neurons - cytology; Motor Neurons - drug effects; Motor Neurons - metabolism; Muscles; Mutation; Neurodegeneration; Oxidation-Reduction; Oxidative stress; Paralysis; Patients; Phenotype; Phosphorylation; Pluripotency; Riboflavin; Riboflavin - metabolism; Stem cells; Superoxide anions; Tubulin; Vitamin B; Vitamin B2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21197402

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 and , 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 Q 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 (Ca ) 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.