Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a worldwide prevalence of about 1%, characterized by impairments in social interaction, communication, repetitive patterns of behaviors, and can be associated with hyper- or hypo-reactivity of sensory stimulation and cognitive disability. ASD comorbid features include internalizing and externalizing symptoms such as anxiety, depression, hyperactivity, and attention problems. The precise etiology of ASD is still unknown and it is undoubted that the disorder is linked to some extent to both genetic and environmental factors. It is also well-documented and known that one of the most striking and consistent finding in ASD is the higher prevalence in males compared to females, with around 70% of ASD cases described being males. The present review looked into the most significant studies that attempted to investigate differences in ASD males and females thus trying to shade some light on the peculiar characteristics of this prevalence in terms of diagnosis, imaging, major autistic-like behavior and sex-dependent uniqueness. The study also discussed sex differences found in animal models of ASD, to provide a possible explanation of the neurological mechanisms underpinning the different presentation of autistic symptoms in males and females.

Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism. As Nrf2 is down-regulated in FRDA, targeting Nrf2-mediated ferroptosis in FRDA may be an attractive option to counteract neurodegeneration in such disease, thus paving the way to new therapeutic opportunities. In this study, we evaluated ferroptosis hallmarks in frataxin-silenced mouse myoblasts, in hearts of a frataxin Knockin/Knockout (KIKO) mouse model, in skin fibroblasts and blood of patients, particularly focusing on ferroptosis-driven gene expression, mitochondrial impairment and lipid peroxidation. The efficacy of Nrf2 inducers to neutralize ferroptosis has been also evaluated.

Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the mammalian brain, essential not only to the development of the central nervous system but also to synaptic plasticity. BDNF is present in various brain areas, but highest levels of expression are seen in the cerebellum and hippocampus. After birth, BDNF acts in the cerebellum as a mitogenic and chemotactic factor, stimulating the cerebellar granule cell precursors to proliferate, migrate and maturate, while in the hippocampus BDNF plays a fundamental role in synaptic transmission and plasticity, representing a key regulator for the long-term potentiation, learning and memory. Furthermore, the expression of BDNF is highly regulated and changes of its expression are associated with both physiological and pathological conditions. The purpose of this review is to provide an overview of the current state of knowledge on the BDNF biology and its neurotrophic role in the proper development and functioning of neurons and synapses in two important brain areas of postnatal neurogenesis, the cerebellum and hippocampus. Dysregulation of BDNF expression and signaling, resulting in alterations in neuronal maturation and plasticity in both systems, is a common hallmark of several neurodevelopmental diseases, such as autism spectrum disorder, suggesting that neuronal malfunction present in these disorders is the result of excessive or reduced of BDNF support. We believe that the more the relevance of the pathophysiological actions of BDNF, and its downstream signals, in early postnatal development will be highlighted, the more likely it is that new neuroprotective therapeutic strategies will be identified in the treatment of various neurodevelopmental disorders.

The estrogen receptor-α (ERα) is a transcription factor that regulates gene expression through the binding to its cognate hormone 17β-estradiol (E2). ERα transcriptional activity is regulated by E2-evoked 26S proteasome-mediated ERα degradation and ERα serine (S) residue 118 phosphorylation. Furthermore, ERα mediates fast cell responses to E2 through the activation of signaling cascades such as the MAPK/ERK and phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog 1 pathways. These E2 rapid effects require a population of the ERα located at the cell plasma membrane through palmitoylation, a dynamic enzymatic modification mediated by palmitoyl-acyl-transferases. However, whether membrane-initiated and transcriptional ERα activities integrate in a unique picture or represent parallel pathways still remains to be firmly clarified. Hence, we evaluated here the impact of ERα palmitoylation on E2-induced ERα degradation and S118 phosphorylation. The lack of palmitoylation renders ERα more susceptible to E2-dependent degradation, blocks ERα S118 phosphorylation and prevents E2-induced ERα estrogen-responsive element-containing promoter occupancy. Consequently, ERα transcriptional activity is prevented and the receptor addressed to the nuclear matrix subnuclear compartment. These data uncover a circuitry in which receptor palmitoylation links E2-dependent ERα degradation, S118 phosphorylation, and transcriptional activity in a unique molecular mechanism. We propose that rapid E2-dependent signaling could be considered as a prerequisite for ERα transcriptional activity and suggest an integrated model of ERα intracellular signaling where E2-dependent early extranuclear effects control late receptor-dependent nuclear actions.

Vitamin B12 (VitB12) is a micronutrient and acts as a cofactor for fundamental biochemical reactions: the synthesis of succinyl-CoA from methylmalonyl-CoA and biotin, and the synthesis of methionine from folic acid and homocysteine. VitB12 deficiency can determine a wide range of diseases, including nervous system impairments. Although clinical evidence shows a direct role of VitB12 in neuronal homeostasis, the molecular mechanisms are yet to be characterized in depth. Earlier investigations focused on exploring the biochemical shifts resulting from a deficiency in the function of VitB12 as a coenzyme, while more recent studies propose a broader mechanism, encompassing changes at the molecular/cellular levels. Here, we explore existing study models employed to investigate the role of VitB12 in the nervous system, including the challenges inherent in replicating deficiency/supplementation in experimental settings. Moreover, we discuss the potential biochemical alterations and ensuing mechanisms that might be modified at the molecular/cellular level (such as epigenetic modifications or changes in lysosomal activity). We also address the role of VitB12 deficiency in initiating processes that contribute to nervous system deterioration, including ROS accumulation, inflammation, and demyelination. Consequently, a complex biological landscape emerges, requiring further investigative efforts to grasp the intricacies involved and identify potential therapeutic targets.

Reactive oxygen species (ROS) is a term that defines a group of unstable compounds derived from exogenous sources or endogenous metabolism. Under physiological conditions, low levels of ROS play a key role in the regulation of signal transduction- or transcription-mediated cellular responses. In contrast, excessive and uncontrolled loading of ROS results in a pathological state known as oxidative stress (OS), a leading contributor to aging and a pivotal factor for the onset and progression of many disorders. Evolution has endowed cells with an antioxidant system involved in stabilizing ROS levels to a specific threshold, maintaining ROS-induced signalling function and limiting negative side effects. In mammals, a great deal of evidence indicates that females defence against ROS is more proficient than males, determining a longer lifespan and lower incidence of most chronic diseases. In this review, we will summarize the most recent sex-related differences in the regulation of redox homeostasis. We will highlight the peculiar aspects of the antioxidant defence in sex-biased diseases whose onset or progression is driven by OS, and we will discuss the molecular, genetic, and evolutionary determinants of female proficiency to cope with ROS.