THE SONIC HEDGEHOG AGONIST SAG ATTENUATES MITOCHONDRIAL DYSFUNCTION AND DECREASES THE NEUROTOXOCITY INDUCED BY FRATAXIN-DEFICIENT ASTROCYTES

Friedreich’s ataxia (FRDA) is predominantly a neurodegenerative disease caused by the deficiency of protein called frataxin (FXN). Although main pathological alterations are observed in neurons, it becoming clear that other non-neuronal cells such as astrocytes may be actively involved process associated with disease. Depending on stimuli they respond to, acquire different activation states astrogliosis. Neuroinflammatory induce formation A1 reactive astrocytes, which upregulate proinflammatory genes, being harmful for neurons. have been detected post-mortem tissue patients disorders, hypothesized might deleterious effects exacerbating process. Recent studies demonstrated positive Sonic Hedgehog (SHH) agonists astrocyte viability and proliferation, astrocyte-mediated neuroprotection, also mitochondrial activity dynamics. As changes important components etiology influence SHH physiology could therapeutic relevance. In this work, we thoroughly characterized reactivity phenotype status FXN-deficient human evaluating well effect reactivity, viability, function. We used an vitro model based short hairpin RNA packaged lentiviral vector, allowed us to decrease FXN levels cortical similar those FRDA patients, found had less cell higher expression several markers, than control cells. Both phenomena were prevented chronic treatment smoothened agonist (SAG), signaling agonist. Moreover, showed defects function dynamics, partially rescued SAG. Regarding possible neuroprotective agonists, previous results able neurodegeneration, SAG attenuated neurotoxicity triggered mouse neurons conditioned medium astrocytes. Overall, our suggest like SAG, target reduce FRDA-associated neurodegeneration.