Untangling the Molecular Mechanisms Contributing to Autism Spectrum Disorder Using Stem Cells

Autism Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Autism spectrum disorder (ASD) is a complex neuro developmental condition characterized by significant genetic and phenotypic variability, making diagnosis treatment challenging. The heterogeneity of ASD-associated variants the absence clear causal factors in many cases complicate personalized care. Traditional models, such as postmortem brain tissue animal studies, have provided valuable insights but are limited capturing dynamic processes human-specific aspects ASD pathology. Recent advances human induced pluripotent stem cell (iPSC) technology transformed research enabling generation patient-derived neural cells both two-dimensional cultures three-dimensional organoid models. These models retain donor's background, allowing researchers to investigate disease-specific cellular molecular mechanisms while identifying potential therapeutic targets tailored individual patients. This commentary highlights how cell-based approaches advancing our understanding paving way for more diagnostic strategies.

Language: Английский

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A Blueprint for Translational Precision Medicine in Autism Spectrum Disorder and Related Neurogenetic Syndromes

Journal of Child and Adolescent Psychopharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Objectives: Despite growing knowledge of the underlying neurobiology autism spectrum disorder (ASD) and related neurogenetic syndromes, treatment discovery has remained elusive. In this review, we provide a blueprint for translational precision medicine in ASD syndromes. Methods: The trofinetide Rett syndrome (RTT) is described, role nonmammalian, mammalian, stem cell model systems identification molecular targets drug screening discussed. We then framework translating preclinical findings to human clinical trials, including biomarkers selecting evaluating target engagement, discuss how leverage these future development. Results: Multiple have been developed, each with tradeoffs regard suitability high-throughput small molecule screening, conservation across species, behavioral face validity. Future trials should incorporate intermediate phenotypes demonstrate engagement. Factors that contributed approval RTT included replicated mouse models, well-studied natural history syndrome, development RTT-specific outcome measures, strong engagement family community. Conclusions: translation our understanding will require approach, use multiple selection, evaluation trial design strategies address heterogeneity, power, placebo response.

Language: Английский

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SCN2A-linked myelination deficits and synaptic plasticity alterations drive auditory processing disorders in ASD

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 28, 2024

Autism spectrum disorder (ASD) is a neurodevelopmental characterized by complex sensory processing deficits. A key unresolved question how alterations in neural connectivity and communication translate into the behavioral manifestations seen ASD. Here, we investigate oligodendrocyte dysfunction alters myelin plasticity neuronal activity, leading to auditory associated with We focus on SCN2A gene, an ASD-risk factor, understand its role myelination within nervous system. Through transcriptional profiling, identified expression of myelin-associated genes Scn2a conditional knockout mice, highlighting cellular consequences engendered deletion oligodendrocytes. The results reveal nuanced interplay between oligodendrocytes axons, where causes intricate process myelination. This disruption instigates changes axonal properties, presynaptic excitability, synaptic at single cell level. Furthermore, oligodendrocyte-specific compromises integrity circuitry pathways, hypersensitivity. Our findings novel pathway linking deficits activity abnormalities

Language: Английский

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More than meets the eye: A conserved sensorimotor reflex helps unravel the circuit mechanisms of ASD

Neuron, Journal Year: 2024, Volume and Issue: 112(9), P. 1375 - 1378

Published: May 1, 2024

Language: Английский

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Crosstalk among WEE1 Kinase, AKT, and GSK3 in Nav1.2 Channelosome Regulation

Published: June 3, 2024

The signaling complex around voltage-gated sodium (Nav) channels includes accessory proteins and kinases crucial for regulating neuronal firing. Previous studies showed that one such kinase, WEE1—critical to the cell cycle—selectively modulates Nav1.2 channel activity through protein fibroblast growth factor 14 (FGF14). Here, we tested whether WEE1 exhibits crosstalk with AKT/GSK3 pathway coordinated regulation of FGF14/Nav1.2 assembly function. Using in-cell split luciferase complementation assay (LCA), found inhibitor II GSK3 XIII reduce formation, while AKT triciribine increases it. However, combining either other two inhibitors abolished its effect on formation. Whole-cell voltage-clamp recordings currents (INa) in HEK293 cells co-expressing FGF14-GFP significantly suppresses peak INa density, both alone presence or XIII, despite latter inhibitors’ opposite effects INa. Additionally, slowed tau fast inactivation, caused depolarizing shifts voltage dependence activation inactivation. These phenotypes prevailed were additive when combined but outcompeted present. Concerted by II, also observed long-term inactivation use-dependence currents. Overall, these findings suggest a role kinase—in concert pathway—in channelosome.

Language: Английский

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White matter; early-intervention services; FMR1 gene

The Transmitter, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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Maternal Immune Activation and Peripubertal Stress Synergistically Disrupt Cerebellar Plasticity Integration and Impair Motor Coordination Learning

Published: Jan. 1, 2024

Language: Английский

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Processing reliant on granule cells is essential for motor learning but dispensable for many cerebellar-dependent behaviors

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 11, 2024

Abstract Cerebellar dysfunction leads to motor, learning, emotional, and social deficits. It is assumed that these deficits arise from impaired processing of mossy fiber inputs activate granule cells (GCs) in turn excite Purkinje (PCs). However, high-frequency spontaneous PC firing might also influence behaviors. To clarify how the cerebellum regulates behaviors, we compared effects disrupting either GC signaling, which selectively perturbs cerebellar processing, or disrupts firing. We find both signaling are required for eyeblink conditioning vestibulo-ocular reflex (VOR) learning. impairs baseline VOR, anxiety, but abolishing does not. This establishes essential motor not many cerebellum-dependent suggests such behaviors could be rescued by elevating downstream targets, as shown previously

Language: Английский

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A patient organization perspective: charting the course to a cure for SCN2A-related disorders

Therapeutic Advances in Rare Disease, Journal Year: 2024, Volume and Issue: 5

Published: Jan. 1, 2024

The SCN2A gene encodes the Nav1.2 protein, a voltage-gated sodium channel crucial for initiating and transmitting action potentials in neurons. Dysfunction Nav1.2, often stemming from genetic mutations gene, leads to SCN2A-related disorders. Individuals harboring pathogenic variants present with severe neurodevelopmental disorders such as epilepsy, autism spectrum disorders, movement cortical visual impairment, intellectual disabilities. FamilieSCN2A Foundation, 501(c)(3) patient advocacy organization, is dedicated enhancing lives of those affected by Fueled vision world effective treatments cures all patients Foundation has charted course cure based on their core values urgency, integrity, collaboration, inclusion. Their strategic plan centers building comprehensive research-readiness infrastructure that maximizes probability bringing curative therapies patients. Appreciating statistically most drug development initiatives will fail, creating an number drugs turn net success achieving vision. Through dynamic notable achievements, including raising ~$6 million USD, funding 26 research grants totaling ~$4.7 forging partnerships across disorder ecosystem foundation actively executing its plan. With advancing rapidly thriving diverse, engaged stakeholders, believes outlook bright.

Language: Английский

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<i>SCN2A</i>-Related Disorders

Cambridge University Press eBooks, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

SCN2A encodes a voltage-gated sodium channel (designated NaV1.2) vital for generating neuronal action potentials. Pathogenic variants are associated with diverse array of neurodevelopmental disorders featuring neonatal or infantile onset epilepsy, developmental delay, autism, intellectual disability and movement disorders. is high confidence risk gene autism spectrum disorder commonly discovered cause epilepsy. This remarkable clinical heterogeneity mirrored by extensive allelic complex genotype-phenotype relationships partially explained divergent functional consequences pathogenic variants. Emerging therapeutic strategies targeted to specific patterns NaV1.2 dysfunction offer hope improving the lives individuals affected SCN2A-related Element provides review features, genetic basis, pathophysiology, pharmacology treatment these conditions authored leading experts in field accompanied perspectives shared families. title also available as Open Access on Cambridge Core.

Language: Английский

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