Redox unbalance modifies neurogenic potential

Reactive oxygen species (ROS), including superoxide anion, hydroxyl radicals and hydrogen peroxide, can be formed endogenously by incomplete reduction of molecular oxygen occurring during mitochondrial oxidative phosphorylation, or by interactions with exogenous sources. The antioxidant defense system, with its major enzymes Catalase, superoxide dismutase (SODs) and glutathione peroxidase (Gpx), has a critical role in counteracting the accumulation of ROS. An imbalance in ROS production and antioxidant capacity leads to oxidative stress. Several pathological conditions, including neurological and neuropsychiatric disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, autism, but also depression, have been associated to the occurrence of oxidative stress. Besides the critical role played in diseases, the cellular redox state influences cell functions and viability. In fact, the modulation of ROS levels represents a major strategy to regulate gene expression, cell proliferation and differentiation already from early development [1].This is related to the redox-responsiveness of several transcription factors (TFs), whose capability to bind DNA is modulated by the oxidation/reduction of critical cysteine residues contained in their DNA binding site [2]. In addition to TFs, the regulation of key signaling pathway requires the generation of ROS that activate essential proteins through the reversible oxidation of key cysteine residues [3]. Increasing evidence points to the critical role played by the ROS-mediated signaling in the regulation of neurogenesis [3], as low non-toxic ROS levels promote self-renewal and regulate the neurogenic potential in neural stem cells [3]. Therefore, misfunction of the antioxidant system and uncontrolled ROS generation may have detrimental consequences for the developing nervous system and even result in an increased predisposition to neurological and psychiatric disorders. Early insults altering the redox state, such as certain xenobiotics contaminating food [4], can lead to long-lasting changes in the structure and function of the developing brain. Another adverse condition altering the ROS balance and leading to long-term pathological outcomes is the developmental exposure to high levels of glucocorticoids (GCs). GCs are steroid hormones critical for the differentiation of many fetal tissues as well as for the physiological response to stress. During pregnancy, the placental 11-β-hydroxysteroid dehydrogenase keeps fetal levels of GCs lower than maternal levels. However, prenatal exposure to excess GCs occurring in case of severe maternal stress, placenta failure or therapeutic treatment, has been shown to modify the development of the nervous system with lifelong adverse effects. Human induced pluripotent stem cells (IPSCs) have been proposed as a powerful in vitro model to investigate …