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Autism spectrum disorders (ASD) affects 1 in 36 children and is characterized by repetitive behaviors and difficulties in social interactions and social communication. The etiology of ASD is extremely heterogeneous, with a large number of ASD cases that are of unknown or complex etiology, which suggests the potential contribution of epigenetic risk factors. In particular, epidemiological and animal model studies suggest that inflammation during pregnancy could lead to an increased risk of ASD in the offspring. However, the molecular mechanisms that contribute to ASD pathogenesis in relation to maternal inflammation during pregnancy in humans are underexplored. Several pro-inflammatory cytokines have been associated with increased autistic-like behaviors in animal models of maternal immune activation, including IL-17A. Using a combination of ASD patient lymphocytes and stem cell-derived human neurons exposed to IL-17A we discovered a shared molecular signature that highlights a metabolic and translational node that could lead to altered neuronal excitability. Further, our work on human neurons brings forward the possibility that defects in the DNA damage response could be underlying the effect of IL-17A on human excitatory neurons, linking exacerbated unrepaired DNA damage to the pathogenicity of maternal inflammation in connection to ASD.

Precise regulation of the chromatin environment through post-translational histone modification modulates transcription and controls brain development. Not surprisingly, mutations in a large number of histone-modifying enzymes underlie complex brain disorders. In particular, the histone methyltransferase ASH1L modifies histone marks linked to transcriptional activation and has been implicated in multiple neuropsychiatric disorders. However, the mechanisms underlying the pathobiology of ASH1L-asociated disease remain underexplored. We generated human isogenic stem cells with a mutation in ASH1L's catalytic domain. We find that ASH1L dysfunction results in reduced neurite outgrowth, which correlates with alterations in the chromatin profile of activating and repressive histone marks, as well as the dysregulation of gene programs important for neuronal structure and function implicated in neuropsychiatric disease. We also identified a novel regulatory node implicating both the SP and Krüppel -like families of transcription factors and ASH1L relevant to human neuronal development. Finally, we rescue cellular defects linked to ASH1L dysfunction by leveraging two independent epigenetic mechanisms that promote transcriptional activation. In summary, we identified an ASH1L-driven epigenetic and transcriptional axis essential for human brain development and complex brain disorders that provide insights into future therapeutic strategies for ASH1L-related disorders.

Neurodevelopmental disorders (NDDs) affect 15% of children and are usually associated with intellectual disability, seizures, and autistic behaviors, among other neurological presentations. Mutations in a wide spectrum of gene families alter key stages of human brain development, leading to defects in neural circuits or brain architecture. Studies in animal systems have provided important insights into the pathobiology of several NDDs. Human stem cell technologies provide a complementary system that allows functional manipulation of human brain cells during developmental stages that would otherwise be inaccessible during human fetal brain development. Therefore, stem cell-based models advance our understanding of human brain development by revealing human-specific mechanisms contributing to the broad pathogenesis of NDDs. We provide a comprehensive overview of the latest research on two and three-dimensional human stem cell-based models. First, we discuss convergent cellular and molecular phenotypes across different NDDs that have been revealed by human iPSC systems. Next, we examine the contribution of in vitro human neural systems to the development of promising therapeutic strategies. Finally, we explore the potential of stem cell systems to draw mechanistic insight for the study of sex dimorphism within NDDs., Competing Interests: Declaration of competing interest The authors declare no financial interests or other interests related to the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Serum tyrosine levels increase during aging, neurocognitive, metabolic, and cardiovascular disorders. However, calorie restriction (CR) and sleep lower serum tyrosine levels. We previously showed that tyrosine inhibits tyrosyl-tRNA synthetase (TyrRS)-mediated activation of poly-ADP-ribose polymerase 1 (PARP1). Here, we show that histone serine-ADP-ribosylation is decreased in Alzheimer's Disease (AD) brains, and increased tyrosine levels deplete TyrRS and cause neuronal DNA damage. However, dopamine and brain-derived neurotrophic factor (BDNF) increase TyrRS and histone serine-ADP-ribosylation. Furthermore, cis-resveratrol (cis-RSV) that binds to TyrRS mimicking a 'tyrosine-free' conformation increases TyrRS, facilitates histone serine-ADP-ribosylation-dependent DNA repair, and provides neuroprotection in a TyrRS-dependent manner. Conversely, trans-RSV that binds to TyrRS mimicking a 'tyrosine-like' conformation decreases TyrRS, inhibits serine-ADP-ribosylation-dependent DNA repair, and induces neurodegeneration in rat cortical neurons. Our findings suggest that age-associated increase in serum tyrosine levels may effect neurocognitive and metabolic disorders and offer a plausible explanation for divergent results obtained in clinical trials using resveratrol., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects. Therefore, the mechanism of action of RSV that elicits beneficial effects remains an enigma. In a previously published work, we demonstrated structural similarities between RSV and tyrosine amino acid. RSV acts as a tyrosine antagonist and competes with it to bind to human tyrosyl-tRNA synthetase (TyrRS). Interestingly, although both isomers of RSV bind to TyrRS, only the cis-isomer evokes a unique structural change at the active site to promote its interaction with poly-ADP-ribose polymerase 1 (PARP1), a major determinant of cellular NAD + -dependent stress response. However, retention of trans-RSV in the active site of TyrRS mimics its tyrosine-bound conformation that inhibits the auto-poly-ADP-ribos(PAR)ylation of PARP1. Therefore, we proposed that cis-RSV-induced TyrRS-regulated auto-PARylation of PARP1 would contribute, at least in part, to the reported health benefits of RSV through the induction of protective stress response. This observation suggested that trans-RSV would inhibit TyrRS/PARP1-mediated protective stress response and would instead elicit an opposite effect compared to cis-RSV. Interestingly, most recent studies also confirmed the conversion of trans-RSV and its metabolites to cis-RSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the auto-PARylation of PARP1 provides a potential molecular basis for the observed dichotomic effects of RSV under different experimental paradigms. However, the fact that natural RSV exists as a diastereomeric mixture of its cis and trans isomers and cis-RSV is also a physiologically relevant isoform has not yet gained much scientific attention.

Resveratrol (RSV) and nicotinamide (NAM) have garnered considerable attention due to their anti-inflammatory and anti-aging properties. NAM is a transient inhibitor of class III histone deacetylase SIRTs (silent mating type information regulation 2 homologs) and SIRT1 is an inhibitor of poly-ADP-ribose polymerase-1 (PARP1). The debate on the relationship between RSV and SIRT1 has precluded the use of RSV as a therapeutic drug. Recent work demonstrated that RSV facilitates tyrosyl-tRNA synthetase (TyrRS)-dependent activation of PARP1. Moreover, treatment with NAM is sufficient to facilitate the nuclear localization of TyrRS that activates PARP1. RSV and NAM have emerged as potent agonists of PARP1 through inhibition of SIRT1. In this study, we evaluated the effects of RSV and NAM on pro-inflammatory macrophages. Our results demonstrate that treatment with either RSV or NAM attenuates the expression of pro-inflammatory markers. Strikingly, the combination of RSV with NAM, exerts additive effects on PARP1 activation. Consistently, treatment with PARP1 inhibitor antagonized the anti-inflammatory effect of both RSV and NAM. For the first time, we report the ability of NAM to augment PARP1 activation, induced by RSV, and its associated anti-inflammatory effects mediated through the induction of BCL6 with the concomitant down regulation of COX-2.