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The lack of effective drugs for autism spectrum disorder (ASD) has prompted researchers to consider common dysregulated pathways in ASD and cancer, including PI3K/AKT/mTOR, Wnt/GSK-3β/β-catenin, Notch, JAK/STAT, and MAPK/ERK signaling. Progress has been made taking some compounds from model systems to clinical trials. Various drugs targeting these signaling pathways have been developed to treat cancer. Repurposing cancer drugs for ASD requires evaluating the dysregulation direction (up or down) and pathway interactions. The variety of causative factors contributing to the clinical heterogeneity of ASD provides a strong incentive for the implementation of precision medicine. However, financial challenges arise due to the small cohort of individuals with specific genetic mutations. Repurposing cancer drugs could indeed prove to be a financially feasible strategy. Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with uncertain origins. Understanding of the mechanisms underlying ASD remains limited, and treatments are lacking. Genetic diversity complicates drug development. Given the complexity and severity of ASD symptoms and the rising number of diagnoses, exploring novel therapeutic strategies is essential. Here, we focus on shared molecular pathways between ASD and cancer and highlight recent progress on the repurposing of cancer drugs for ASD treatment, such as mTOR inhibitors, histone deacetylase inhibitors, and anti-inflammatory agents. We discuss how to improve trial design considering drug dose and patient age. Lastly, the discussion explores the critical aspects of side effects, commercial factors, and the efficiency of drug-screening pipelines; all of which are essential considerations in the pursuit of repurposing cancer drugs for addressing core features of ASD. Understanding of the mechanisms underlying ASD remains limited, and treatments are lacking. Given the complexity and severity of ASD symptoms and the rising number of diagnoses, exploring novel therapeutic strategies is essential. Here, we focus on shared molecular pathways between ASD and cancer and highlight recent progress on the repurposing of cancer drugs for ASD treatment. We discuss how to improve trial design considering drug dose and patient age. Lastly, the discussion explores the critical aspects of side effects, commercial factors, and the efficiency of drug-screening pipelines; all of which are essential considerations in the pursuit of repurposing cancer drugs for addressing core features of ASD. [ABSTRACT FROM AUTHOR]

Mutations in epigenetic factors are associated with autism spectrum disorder (ASD). In this issue of Neuron , Yan et al. (2022) show that the antagonism of ASH1L and PRC2 switches the equilibrium of histone methylation at the ephrin receptor A7 locus, causing decreased EphA7 expression, deficits in synaptic pruning, and ASD-like behaviors. [ABSTRACT FROM AUTHOR]

Background: Friedreich's ataxia is an autosomal-recessive cerebellar ataxia caused by mutation of the frataxin gene, resulting in decreased frataxin expression, mitochondrial dysfunction, and oxidative stress. Currently, no treatment is available for Friedreich's ataxia patients. Given that levels of residual frataxin critically affect disease severity, the main goal of a specific therapy for Friedreich's ataxia is to increase frataxin levels.Objectives: With the aim to accelerate the development of a new therapy for Friedreich's ataxia, we took a drug repositioning approach to identify market-available drugs able to increase frataxin levels.Methods: Using a cell-based reporter assay to monitor variation in frataxin amount, we performed a high-throughput screening of a library containing 853 U.S. Food and Drug Administration-approved drugs.Results: Among the potentially interesting candidates isolated from the screening, we focused our attention on etravirine, an antiviral drug currently in use as an anti-human immunodeficiency virus therapy. Here, we show that etravirine can promote a significant increase in frataxin levels in cells derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA translation. Importantly, frataxin accumulation in treated patient cell lines is comparable to frataxin levels in unaffected carrier cells, suggesting that etravirine could be therapeutically relevant. Indeed, etravirine treatment restores the activity of the iron-sulphur cluster containing enzyme aconitase and confers resistance to oxidative stress in cells derived from Friedreich's ataxia patients.Conclusions: Considering its excellent safety profile along with its ability to increase frataxin levels and correct some of the disease-related defects, etravirine represents a promising candidate as a therapeutic for Friedreich's ataxia. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is fragile X syndrome (FXS), an NDD caused by the absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composition of postsynaptic density (PSD) contributes to FXS. In the striatum, the FXS mouse model shows an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, which is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes. [Display omitted] • FXS striatal PSDs show a decrease in a set of actin-related proteins • Impaired striatal synaptic actin dynamics affects dendritic spine morphology • FXS-related inflexibility is caused by striatal dysfunctions • Spine deficits and behavioral inflexibility are ameliorated, boosting actin dynamics Mercaldo et al. demonstrate a role of striatum in fragile X syndrome (FXS). The mouse model of FXS displays deficits in actin composition and dynamics at striatal synapses, reflecting structural deficits of dendritic spines and specific behavioral impairments. Restoring actin dynamics in the striatum improves FXS-related pathology and behavioral deficits. [ABSTRACT FROM AUTHOR]

The article presents the discussion on centrosome being an interaction hub composed of two centrioles surrounded by pericentriolar material. Topics include centrosome acting as the main microtubule-organizing center (MTOC) in many cells containing stem and progenitor cells; and inducing pluripotent stem cell–derived neural stem cells and neurons reproducibly determining the interactome with mass spectrometry.