Friedreich's Ataxia (FRDA) is an early onset hereditary disorder with a strong neurodegenerative component caused by repeat expansions on the gene encoding for frataxin (FXN) that result in FXN defici Show more
Friedreich's Ataxia (FRDA) is an early onset hereditary disorder with a strong neurodegenerative component caused by repeat expansions on the gene encoding for frataxin (FXN) that result in FXN deficiency. This deficit has been linked to a cascade of biochemical alterations, including mitochondrial dysfunction, oxidative stress and neuronal apoptosis, that drives the neurodegenerative process. FRDA is a very incapacitating disease and patients rely on very limited therapeutic alternatives, such as the recently approved drug omaveloxolone, to treat the oxidative stress. Nevertheless, previous studies have suggested the activation of the brain-derived neurotrophic factor (BDNF) may be a promising treatment to regulate FRDA pathophysiology. Herein, we characterize the effects of FXN deficiency in an in vitro model of primary cerebellar granule neurons (CGNs) derived from the FRDA mouse model YG8-800, as well as the therapeutic potential of BDNF partial agonism by the small molecule 7,8-dihydroxyflavone (7,8-DHF). We found evidence of mitochondrial dysfunction concomitant with DNA damage and enhanced cell death due to FXN deficiency in cultured neurons. The treatment with 7,8-DHF was able to reduce the markers of genotoxicity and apoptosis, without restoring the impaired mitochondrial function nor the total cell death, possibly through ferroptosis, revealing a partial neuroprotective effect insufficient to halt the neurodegenerative process in this in vitro model of FRDA. Show less
Extremely low-frequency (ELF) magnetic fields generated by power-line sources are ubiquitous, yet their long-term effects on neuronal cells remain unclear. We investigated whether continuous exposure Show more
Extremely low-frequency (ELF) magnetic fields generated by power-line sources are ubiquitous, yet their long-term effects on neuronal cells remain unclear. We investigated whether continuous exposure (72 - 96 h) to a 60 Hz ELF magnetic field induces oxidative DNA damage and alters cell death pathways in differentiated SH-SY5Y human neuroblastoma cells. Neuron-like cells generated by retinoic acid and brain-derived neurotrophic factor were exposed to 1-3 mT ELF magnetic fields for 96 h, with sham-exposed cells as controls. Chromosomal integrity (Hoechst 33258 staining), apoptosis/necrosis (Annexin V-FITC/propidium iodide flow cytometry), oxidative DNA damage (apurinic/apyrimidinic site analysis), and redox balance (total oxidant and total antioxidant status) were assessed. ELF magnetic field exposure caused intensity dependent nuclear abnormalities, increased oxidative DNA lesions, early oxidative imbalance, and a predominance of necrotic over apoptotic cell death. These findings indicate that continuous low-intensity ELF magnetic field exposure disrupts redox homeostasis and compromises genomic stability in differentiated neuronal cells. Show less