Jul 2026· Proceedings of the National Academy of Sciences of the United States of America· Vol 123 31, pp.
e2605483123
· 0 citations· 39 references
Medicine
TL;DR
The findings implicate disrupted SYTL4-RAB27A-dependent vesicle trafficking in ASD pathogenesis and identify SYTL4 and RAB27A as previously unrecognized contributors to autism-associated synaptic deficits and behavior.
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and repetitive behaviors, with genetic studies implicating widespread synaptic dysfunction. However, the contribution of presynaptic vesicle trafficking mechanisms to ASD pathogenesis remains incompletely understood. Here, we identify synaptotagmin-like protein 4 (SYTL4), a RAB27A effector previously characterized in secretory cells, as a regulator of presynaptic function in the mammalian brain. We report a recurrent hemizygous missense variant, R126H, located within the Rab-binding domain of SYTL4 in four unrelated male individuals, consistent with an X-linked recessive mode of ASD, and additionally identify a de novo missense variant in RAB27A (T41A) in an independent ASD family that affects a domain mediating interactions with downstream effectors. Using a R126H knock-in mouse model, we show that R126H knock-in male mice exhibit ASD-relevant behavioral abnormalities accompanied by synaptic deficits in the medial prefrontal cortex. At the molecular level, ASD-associated SYTL4 and RAB27A variants interfere with the interaction between SYTL4 and RAB27A, providing a mechanistic link between human genetic variation and synaptic dysfunction. Together, these findings implicate disrupted SYTL4-RAB27A-dependent vesicle trafficking in ASD pathogenesis and identify SYTL4 and RAB27A as previously unrecognized contributors to autism-associated synaptic deficits and behavior.
The concept that NRXN1 deletions alone do not determine clinical outcome but rather act within a broader genetic and biological context is supported, whereby NRXN1 deletions act as susceptibility factors whose phenotypic consequences are shaped by additional genetic and modifying influences.
N. Kastratović, Marina Gazdić Janković, Marina Miletić Kovačević et al.· International Journal of Mol...· 0 citations
This work establishes the first domain-resolved in vivo rodent models of NEDBA and provides a validated translational platform for mechanistic investigation and preclinical therapeutic testing.
Camerron M. Crowder, Lyndsay R Watkins, Alexa R. Geltzeiler et al.· bioRxiv· 0 citations
Evidence is provided that biallelic GIT1 variants affecting transcript processing or causing premature termination underlie a syndromic neurodevelopmental disorder and an essential role for GIT1 in development and cognitive function is established.
P. Failla, V. Muto, Antonella Lauri et al.· Brain : a journal of neurolo...· 0 citations
De novo variants in the ubiquitin-proteasome pathway are linked to autism spectrum disorder (ASD), yet their functional impact on neurodevelopment remains poorly understood. We investigated USP15, a deubiquitinating enzyme with rare damaging variants identified in individuals with ASD, using isogenic human iPSC-derived brain organoids and single-cell transcriptomics. USP15-mutant organoids showed genotype-dependent, progenitor-centered alterations during corticogenesis. Heterozygous organoids modeling haploinsufficiency displayed a shift toward later pseudotime states together with altered maturation and synaptic organization of deep-layer neurons. In contrast, homozygous organoids showed broader phenotypes, including mitotic suppression, aberrant HOX gene expression, and stress-response activation. Regulon analysis showed reduced activity of progenitor-associated regulons, including SOX2, NR2F1, and NR2F2, in heterozygous organoids, whereas homozygous organoids exhibited broader changes in transcriptional regulatory networks. Furthermore, USP15 mutant-associated gene expression patterns were significantly enriched for established ASD risk genes. Comparison with the mouse brain perturbation atlas showed that the transcriptional signature of the USP15 mutant showed notable overlap with those of Fezf2 and Foxp1 mutants, key regulators of deep-layer projection neuron identity. These findings characterize genotype-dependent neurodevelopmental phenotypes associated with reduced USP15 dosage and provide a human neural framework for investigating ASD-relevant developmental mechanisms in the context of a rare ubiquitin-pathway variant.
Tae-Hwan Park, I. Koh, Seoyoung Sung et al.· Molecules and Cells· 0 citations
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and restricted repetitive behaviors. Genetic studies have implicated chromosomal microdeletions in the 8p23.2-pter region in ASD and related disorders, highlighting FBXO25 as a candidate gene. FBXO25 encodes an F-box protein component of the SCF E3 ubiquitin ligase complex, which is involved in protein degradation through the ubiquitin-proteasome system. To investigate the impact of FBXO25 deletion, we generated Fbxo25-deficient mice and conducted behavioral, structural, molecular, transcriptomic, and proteomic analyses. Homozygous Fbxo25 mutant mice exhibited excessive self-grooming, a core ASD-related repetitive behavior. In contrast, both heterozygous and homozygous mice displayed impaired recognition memory in the novel object recognition test. However, social behaviors, anxiety-like responses, and spatial memory were preserved. Golgi staining revealed reduced dendritic complexity in hippocampal dentate gyrus granule cells of both heterozygous and homozygous mice. Western blotting revealed altered protein expression, including decreased PSD95 and CaMKII alpha, and elevated Arc in homozygous mice. Transcriptomic and proteomic analyses identified 17 differentially expressed proteins (DEPs) shared between heterozygous and homozygous mutants, supporting a model of FBXO25 haploinsufficiency. Many DEPs are involved in focal adhesion, cytoskeletal organization, synaptic transmission and signaling, oxidative stress, and protein degradation. These findings suggest that FBXO25 deletion impairs ubiquitin-mediated degradation, leading to synaptic dysfunction and ASD-relevant phenotypes. Our study establishes a novel mouse model of FBXO25 deficiency. It provides mechanistic insight into how disrupted protein degradation may contribute to ASD pathogenesis, highlighting protein degradation as a potential therapeutic target.
Szu-Yu Lin, Ho-Ching Chang, Ya-Han Chang et al.· Progress in neurobiology· 0 citations
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unclear pathogenesis. Growing evidence implicates excitatory/inhibitory (E/I) imbalance in ASD pathophysiology, prompting an investigation into gamma-aminobutyric acid (GABA)-mediated inhibitory transmission. The transcription factor Paired Box 2 (Pax2), essential for GABAergic interneuron specification, participates in the regulation of neural developmental processes. Our previous work demonstrated an E/I imbalance in the neurotransmitter system and reduced GABAARα2-positive neurons in the prefrontal cortex (PFC) of Pax2 neuron-specific deletion mice, though the internal molecular regulatory mechanism remained elusive. In this study, we generated GABAergic neuron-specific Pax2 knockdown mice via injection of AAV-shPax2 virus and comprehensively evaluated ASD-related behaviors, revealing autism-like behaviors, such as impaired social novelty and repetitive behaviors. Molecular analysis revealed upregulation of Tcf7l2, a key downstream mediator of the Wnt/β-catenin signaling pathway. Functional assessment confirmed hyperactivation of the Wnt/β-catenin signaling pathway in GABAergic neuron Pax2 knockdown mice. Notably, pharmacological intervention with esculetin, an inhibitor of the Wnt/β-catenin pathway, ameliorated the observed autism-like behaviors. These findings establish a pathogenic axis wherein GABAergic neuron-specific Pax2 deficiency induces hyperactivation of the Wnt/β-catenin signaling pathway and disrupts E/I balance, ultimately driving autism-like behavioral phenotypes. Our results further identify inhibition of Wnt/β-catenin signaling as a promising therapeutic strategy for ASD.