LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

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Alternative splicing landscape of the neural transcriptome in a cytoplasmic-predominant Pten expression murine model of autism-like Behavior

Translational Psychiatry ◽

10.1038/s41398-020-01068-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Stetson Thacker ◽

Marilyn Sefyi ◽

Charis Eng

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Murine Model ◽

Neurodevelopmental Disorders ◽

Autism Spectrum ◽

Splicing Factors ◽

Sequencing Data ◽

Central Nervous Systems ◽

Functional Complexity ◽

The Brain

Abstract Alternative splicing (AS) is a posttranscriptional mechanism regulating gene expression that complex organisms utilize to expand proteome diversity from a comparatively limited set of genes. Recent research has increasingly associated AS with increased functional complexity in the central nervous systems in higher order mammals. This work has heavily implicated aberrant AS in several neurocognitive and neurodevelopmental disorders, including autism. Due to the strong genetic association between germline PTEN mutations and autism spectrum disorder (ASD), we hypothesized that germline PTEN mutations would alter AS patterns, contributing to the pathophysiology of ASD. In a murine model of constitutional mislocalization of Pten, recapitulating an autism-like phenotype, we found significant changes in AS patterns across the neural transcriptome by analyzing RNA-sequencing data with the program rMATS. A few hundred significant alternative splicing events (ASEs) that differentiate each m3m4 genotype were identified. These ASEs occur in genes enriched in PTEN signaling, inositol metabolism, and several other pathways relevant to the pathophysiology of ASD. In addition, we identified expression changes in several splicing factors known to be enriched in the nervous system. For instance, the master regulator of microexons, Srrm4, has decreased expression, and consequently, we found decreased inclusion of microexons in the Ptenm3m4/m3m4 cortex (~10% decrease). We also demonstrated that the m3m4 mutation disrupts the interaction between Pten and U2af2, a member of the spliceosome. In sum, our observations point to germline Pten disruption changing the landscape of alternative splicing in the brain, and these changes may be relevant to the pathogenesis and/or maintenance of PTEN-ASD phenotypes.

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FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09358-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Reymundo Lozano ◽

Catherine Gbekie ◽

Paige M. Siper ◽

Shubhika Srivastava ◽

Jeffrey M. Saland ◽

...

Keyword(s):

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Medical Assessment ◽

Forkhead Box ◽

Organ Systems ◽

Practice Parameters ◽

Assessment And Monitoring ◽

Multidisciplinary Group ◽

The Brain

AbstractFOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.

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Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

Scientific Reports ◽

10.1038/s41598-021-86041-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Joseph J. Rossi ◽

Jill A. Rosenfeld ◽

Katie M. Chan ◽

Haley Streff ◽

Victoria Nankivell ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Protein Function ◽

Transcriptional Activity ◽

Neurodevelopmental Disorder ◽

Complete Loss ◽

Loss Of Function ◽

Targeted Disruption ◽

Clinical Exome Sequencing ◽

Partner Protein ◽

The Brain

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

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Graph Ricci Curvatures Reveal Disease-related Changes in Autism Spectrum Disorder

10.1101/2021.11.28.470231 ◽

2021 ◽

Author(s):

Pavithra Elumalai ◽

Yasharth Yadav ◽

Nitin Williams ◽

Emil Saucan ◽

Jürgen Jost ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Resting State ◽

Neurodevelopmental Disorders ◽

Data Exchange ◽

Meta Analysis ◽

Resting State Fmri ◽

Brain Regions ◽

Autism Spectrum ◽

Spectrum Disorder ◽

The Brain

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders that pose a significant global health burden. Measures from graph theory have been used to characterise ASD-related changes in resting-state fMRI functional connectivity networks (FCNs), but recently developed geometry-inspired measures have not been applied so far. In this study, we applied geometry-inspired graph Ricci curvatures to investigate ASD-related changes in resting-state fMRI FCNs. To do this, we applied Forman-Ricci and Ollivier-Ricci curvatures to compare networks of ASD and healthy controls (N = 1112) from the Autism Brain Imaging Data Exchange I (ABIDE-I) dataset. We performed these comparisons at the brain-wide level as well as at the level of individual brain regions, and further, determined the behavioral relevance of region-specific differences with Neurosynth meta-analysis decoding. We found brain-wide ASD-related differences for both Forman-Ricci and Ollivier-Ricci curvatures. For Forman-Ricci curvature, these differences were distributed across 83 of the 200 brain regions studied, and concentrated within the Default Mode, Somatomotor and Ventral Attention Network. Meta-analysis decoding identified the brain regions showing curvature differences as involved in social cognition, memory, language and movement. Notably, comparison with results from previous non-invasive stimulation (TMS/tDCS) experiments revealed that the set of brain regions showing curvature differences overlapped with the set of brain regions whose stimulation resulted in positive cognitive or behavioural outcomes in ASD patients. These results underscore the utility of geometry-inspired graph Ricci curvatures in characterising disease-related changes in ASD, and possibly, other neurodevelopmental disorders.

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Single cell 3’UTR analysis identifies changes in alternative polyadenylation throughout neuronal differentiation and in autism

10.1101/2020.08.12.247627 ◽

2020 ◽

Author(s):

Manuel Göpferich ◽

Nikhil Oommen George ◽

Ana Domingo Muelas ◽

Alex Bizyn ◽

Rosa Pascual ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Neural Stem Cells ◽

Single Cell ◽

Neuronal Differentiation ◽

Mrna Translation ◽

Autism Spectrum ◽

Adult Brain ◽

Control Of Gene Expression ◽

Risk Genes

SUMMARYAutism spectrum disorder (ASD) is a neurodevelopmental disease affecting social behavior. Many of the high-confident ASD risk genes relate to mRNA translation. Specifically, many of these genes are involved in regulation of gene expression for subcellular compartmentalization of proteins1. Cis-regulatory motifs that often localize to 3’- and 5’-untranslated regions (UTRs) offer an additional path for posttranscriptional control of gene expression. Alternative cleavage and polyadenylation (APA) affect 3’UTR length thereby influencing the presence or absence of regulatory elements. However, APA has not yet been addressed in the context of neurodevelopmental disorders. Here we used single cell 3’end sequencing to examine changes in 3’UTRs along the differentiation from neural stem cells (NSCs) to neuroblasts within the adult brain. We identified many APA events in genes involved in neurodevelopment, many of them being high confidence ASD risk genes. Further, analysis of 3’UTR lengths in single cells from ASD and healthy individuals detected longer 3’UTRs in ASD patients. Motif analysis of modulated 3’UTRs in the mouse adult neurogenic lineage and ASD-patients revealed enrichment of the cytoplasmic and polyadenylation element (CPE). This motif is bound by CPE binding protein 4 (CPEB4). In human and mouse data sets we observed co-regulation of CPEB4 and the CPEB-binding synaptic adhesion molecule amyloid beta precursor-like protein 1 (APLP1). We show that mice deficient in APLP1 show aberrant regulation of APA, decreased number of neural stem cells, and autistic-like traits. Our findings indicate that APA is used for control of gene expression along neuronal differentiation and is altered in ASD patients.

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Neurodevelopmental Trajectories and Clinical Profiles in a Sample of Children and Adolescents With Early- and Very-Early-Onset Schizophrenia

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.662093 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maria Pontillo ◽

Roberto Averna ◽

Maria Cristina Tata ◽

Fabrizia Chieppa ◽

Maria Laura Pucciarini ◽

...

Keyword(s):

Children And Adolescents ◽

Neurodevelopmental Disorders ◽

Early Onset ◽

Social Role ◽

Treatment Plan ◽

Neurodevelopmental Disorder ◽

Communication Disorders ◽

Autism Spectrum ◽

Early Onset Schizophrenia ◽

Assessment And Treatment

Schizophrenia before the age of 18 years is usually divided into two categories. Early-onset schizophrenia (EOS) presents between the ages of 13 and 17 years, whereas very-early-onset schizophrenia (VEOS) presents at or before the age of 12 years. Previous studies have found that neurodevelopmental difficulties in social, motor, and linguistic domains are commonly observed in VEOS/EOS patients. Recent research has also shown a high prevalence of neurodevelopmental disorders (e.g., intellectual disability, communication disorders, autism spectrum disorder, neurodevelopmental motor disorders) in VEOS/EOS patients, indicating genetic overlap between these conditions. These findings lend support to the neurodevelopmental continuum model, which holds that childhood neurodevelopmental disorders and difficulties and psychiatric disorders (e.g., schizophrenia) fall on an etiological and neurodevelopmental continuum, and should not be considered discrete entities. Based on this literature, in this study we focused on the overlap between neurodevelopmental disorders and schizophrenia investigating, in a large sample (N = 230) of VEOS/EOS children and adolescents, the clinical differences, at the onset of psychosis, between VEOS/EOS with neurodevelopmental disorder or neurodevelopmental difficulties and VEOS/EOS with no diagnosed neurodevelopmental disorder or neurodevelopmental difficulties. The findings showed that, in children and adolescents with a neurodevelopmental disorder or neurodevelopmental difficulties, psychosis onset occurred at an earlier age, was associated with more severe functional impairment (e.g., global, social, role), and was characterized by positive symptoms (e.g., grandiose ideas, perceptual abnormalities, disorganized communication) and disorganized symptoms (e.g., odd behavior or appearance, bizarre thinking). Instead, in children and adolescents without a neurodevelopmental disorder or neurodevelopmental difficulties, psychosis onset was mainly characterized by negative symptomatology (e.g., social anhedonia, avolition, expression of emotion, experience of emotions and self, ideational richness). Given these differences, the presence of a neurodevelopmental disorder or neurodevelopmental difficulties should be carefully investigated and integrated early into the assessment and treatment plan for VEOS/EOS patients.

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Attention-deficit/hyperactivity disorder and risk for psychiatric and neurodevelopmental disorders in siblings

Psychological Medicine ◽

10.1017/s0033291718000521 ◽

2018 ◽

Vol 49 (1) ◽

pp. 84-91 ◽

Cited By ~ 4

Author(s):

Elina Jokiranta-Olkoniemi ◽

Keely Cheslack-Postava ◽

Petteri Joelsson ◽

Auli Suominen ◽

Alan S. Brown ◽

...

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Neurodevelopmental Disorders ◽

Neurodevelopmental Disorder ◽

Population Based ◽

Autism Spectrum ◽

Schizophrenia Spectrum Disorders ◽

Hyperactivity Disorder ◽

Increased Risk ◽

Spectrum Disorders

AbstractBackgroundProbands with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for several psychiatric and neurodevelopmental disorders. The risk of these disorders among the siblings of probands has not been thoroughly assessed in a population-based cohort.MethodsEvery child born in Finland in 1991–2005 and diagnosed with ADHD in 1995–2011 were identified from national registers. Each case was matched with four controls on sex, place, and date of birth. The full siblings of the cases and controls were born in 1981–2007 and diagnosed in 1981–2013. In total, 7369 cases with 12 565 siblings and 23 181 controls with 42 753 siblings were included in the analyses conducted using generalized estimating equations.Results44.2% of the cases and 22.2% of the controls had at least one sibling diagnosed with any psychiatric or neurodevelopmental disorder (risk ratio, RR = 2.1; 95% CI 2.0–2.2). The strongest associations were demonstrated for childhood-onset disorders including ADHD (RR = 5.7; 95% CI 5.1–6.3), conduct and oppositional disorders (RR = 4.0; 95% CI 3.5–4.5), autism spectrum disorders (RR = 3.9; 95% CI 3.3–4.6), other emotional and social interaction disorders (RR = 2.7; 95% CI 2.4–3.1), learning and coordination disorders (RR = 2.6; 95% CI 2.4–2.8), and intellectual disability (RR = 2.4; 95% CI 2.0–2.8). Also, bipolar disorder, unipolar mood disorders, schizophrenia spectrum disorders, other neurotic and personality disorders, substance abuse disorders, and anxiety disorders occurred at increased frequency among the siblings of cases.ConclusionsThe results offer potential utility for early identification of neurodevelopmental and psychiatric disorders in at-risk siblings of ADHD probands and also argue for more studies on common etiologies.

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The epigenetic regulation of synaptic genes contributes to the etiology of autism

Reviews in the Neurosciences ◽

10.1515/revneuro-2021-0014 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Annamaria Srancikova ◽

Zuzana Bacova ◽

Jan Bakos

Keyword(s):

Epigenetic Regulation ◽

Neurodevelopmental Disorders ◽

Autism Spectrum ◽

Prader Willi Syndrome ◽

Epigenetic Mechanisms ◽

Substantial Evidence ◽

Autistic Symptoms ◽

Spectrum Disorders ◽

The Brain

Abstract Epigenetic mechanisms greatly affect the developing brain, as well as the maturation of synapses with pervasive, long-lasting consequences on behavior in adults. Substantial evidence exists that implicates dysregulation of epigenetic mechanisms in the etiology of neurodevelopmental disorders. Therefore, this review explains the role of enzymes involved in DNA methylation and demethylation in neurodevelopment by emphasizing changes of synaptic genes and proteins. Epigenetic causes of sex-dependent differences in the brain are analyzed in conjunction with the pathophysiology of autism spectrum disorders. Special attention is devoted to the epigenetic regulation of the melanoma-associated antigen-like gene 2 (MAGEL2) found in Prader-Willi syndrome, which is known to be accompanied by autistic symptoms.

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Automatic Detection and Assessment of Autism Spectrum Disorder

Advances in Early Childhood and K-12 Education - Handbook of Research on Critical Issues in Special Education for School Rehabilitation Practices ◽

10.4018/978-1-7998-7630-4.ch020 ◽

2021 ◽

pp. 396-425

Author(s):

Thanga Aarthy M. ◽

Menaka R. ◽

Karthik R.

Keyword(s):

Autism Spectrum Disorder ◽

Early Detection ◽

Early Diagnosis ◽

Neurodevelopmental Disorders ◽

Pathological Condition ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Attention Deficit Hyperactive Disorder ◽

Clinical Methods

Children with neurodevelopmental disorders are increasing gradually every year. One in 100 children are diagnosed with brain function disorder. There are wide categories of disorder such as attention deficit hyperactive disorder, learning, autism spectrum disorder (ASD), etc. In this work, the focus is on ASD, its clinical methods, and analysis in various research works. ASD is a neurodevelopmental disorder which affects the intellectual functioning, social interaction (adaptive behavior), and has a specific obsessive interest. At present, there is no known cure for ASD, but the level of the pathological condition can be reduced when it is detected early. Early detection is tough and challenging till date. Many researches were carried out to ease the early detection for clinicians. Each method has its own merits and demerits. This chapter reviews and condenses various research works and their efficacy in analysis for the early diagnosis and improvement in children with autism.

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The Interplay between Long Noncoding RNAs and Proteins of the Epigenetic Machinery in Ovarian Cancer

Cancers ◽

10.3390/cancers12092701 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2701

Author(s):

Naiade Calanca ◽

Cecilie Abildgaard ◽

Cláudia Aparecida Rainho ◽

Silvia Regina Rogatto

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Noncoding Rnas ◽

Response To Therapy ◽

Long Noncoding Rnas ◽

Cancer Type ◽

Aberrant Expression ◽

Term Survival ◽

Control Of Gene Expression ◽

Epigenetic Machinery

Comprehensive large-scale sequencing and bioinformatics analyses have uncovered a myriad of cancer-associated long noncoding RNAs (lncRNAs). Aberrant expression of lncRNAs is associated with epigenetic reprogramming during tumor development and progression, mainly due to their ability to interact with DNA, RNA, or proteins to regulate gene expression. LncRNAs participate in the control of gene expression patterns during development and cell differentiation and can be cell and cancer type specific. In this review, we described the potential of lncRNAs for clinical applications in ovarian cancer (OC). OC is a complex and heterogeneous disease characterized by relapse, chemoresistance, and high mortality rates. Despite advances in diagnosis and treatment, no significant improvements in long-term survival were observed in OC patients. A set of lncRNAs was associated with survival and response to therapy in this malignancy. We manually curated databases and used bioinformatics tools to identify lncRNAs implicated in the epigenetic regulation, along with examples of direct interactions between the lncRNAs and proteins of the epigenetic machinery in OC. The resources and mechanisms presented herein can improve the understanding of OC biology and provide the basis for further investigations regarding the selection of novel biomarkers and therapeutic targets.

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