Molecular basis of the CYFIP2 and NCKAP1 autism‐linked variants in the WAVE regulatory complex DOI Creative Commons
Song Xie, Ke Zuo, Silvia De Rubeis

и другие.

Protein Science, Год журнала: 2024, Номер 34(1)

Опубликована: Дек. 11, 2024

The WAVE regulatory pentameric complex regulates actin remodeling. Two components of it (CYFIP2 and NCKAP1) are encoded by genes whose genetic mutations increase the risk for autism spectrum disorder (ASD) related neurodevelopmental disorders. Here, we use a newly developed computational protocol hotspot analysis to uncover functional impact these at interface correct isoforms two proteins into complex. turn out be located on surfaces involving largest number hotspots Most them decrease affinity rest complex, but some have opposite effect. results fully consistent with available experimental data. observed changes in stability might activation ultimately play role aberrant pathway leading cell derangement associated disease.

Язык: Английский

Single-cell and spatial transcriptomics: Bridging current technologies with long-read sequencing DOI
Chengwei Ulrika Yuan, Fu Xiang Quah, Martin Hemberg

и другие.

Molecular Aspects of Medicine, Год журнала: 2024, Номер 96, С. 101255 - 101255

Опубликована: Фев. 17, 2024

Язык: Английский

Процитировано

6
DEAD/DEAH-box RNA helicases shape the risk of neurodevelopmental disorders DOI

Chiara Fiorenzani,

Adele Mossa,

Silvia De Rubeis

и другие.

Trends in Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Exploring the connection between RNA splicing and intellectual disability DOI Creative Commons
Anthony Caputo, Ashleigh E. Schaffer

Current Opinion in Genetics & Development, Год журнала: 2025, Номер 91, С. 102322 - 102322

Опубликована: Фев. 8, 2025

Intellectual disability (ID) is a broad diagnostic category that encompasses individuals with impaired cognitive ability. While these disorders have heterogeneous causes, recent developments in next-generation sequencing (NGS) are revealing the prevalence of genetic etiologies. In particular, germline mutations genes affect RNA splicing increasingly common causes ID disorders. Research to elucidate functional relationship between and neurodevelopment critical since molecular therapeutics require nuanced understanding pathological mechanism. this review, we first summarize trends led discovery splicing-ID relationship, then discuss progress future directions for research surrounding neurodevelopment. Finally, speak on how results may serve as foundation burgeoning therapies.

Язык: Английский

Процитировано

0
A neuro-immune axis of transcriptomic dysregulation within the subgenual anterior cingulate cortex in schizophrenia DOI Creative Commons
Rachel L. Smith, Ágoston Mihalik, Nirmala Akula

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 16, 2025

Many genes are linked to psychiatric disorders, but genome-wide association studies (GWAS) and differential gene expression (DGE) analyses in post-mortem brain tissue often implicate distinct sets. This disconnect impedes therapeutic development, which relies on integrating genetic genomic insights. We address this issue using a novel multivariate technique that reduces DGE bias by leveraging co-expression networks controlling for confounds such as drug exposure. Deep RNA sequencing was performed bulk sgACC from individuals with bipolar disorder (BD; N=35), major depression (MDD; N=51), schizophrenia (SCZ; N=44), controls (N=55). Toxicology data dimensionality reduced multiple correspondence analysis; case-control then analyzed 1) traditional 2) group regularized canonical correlation analysis (GRCCA) - regression method accounts feature interdependence. Gene set enrichment compared results established neuropsychiatric risk genes, ontology pathways, cell type enrichments. GRCCA revealed significant SCZ ( P perm =0.001; no BD or MDD association), the resulting weight vector correlated SCZ-control t-statistics R =0.53; <0.05). Both methods indicated down-regulation of immune microglial upregulation ion transport excitatory neuron genes. However, at both transcript level showed stronger enrichments (FDR<0.05). Notably, were enriched GWAS-implicated (FDR<0.05), while not. These findings identify SCZ-specific pattern highlights implicates neuro-immune thus demonstrating utility approaches integrate signals.

Язык: Английский

Процитировано

0
TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons DOI Creative Commons
Marco Flores‐Méndez,

Jesus A Tintos-Hernández,

Leonardo Ramos-Rodriguez

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 7, 2025

ABSTRACT Monogenic pediatric neurodegenerative disorders can reveal fundamental cellular mechanisms that underlie selective neuronal vulnerability. TBCK-Encephaloneuronopathy (TBCKE) is a rare autosomal recessive disorder caused by stop-gain variants in the TBCK gene. Clinically, patients show evidence of profound neurodevelopmental delays, but also symptoms progressive encephalopathy and motor neuron disease. Yet, physiological role protein remains unclear. We report human TBCKE model, derived from iPSCs homozygous for Boricua variant (p.R126X). Using unbiased proteomic analyses neurons, we find interacts with PPP1R21, C12orf4, Cryzl1, consistent being part FERRY mRNA transport complex. Loss leads to depletion C12ORF4 levels across multiple cell types, suggesting may play regulating at least some members preferentially, not exclusively, localizes surface endolysosomal vesicles colocalize lysosomes. Furthermore, TBCK-deficient neurons have reduced content axonal compartment relative soma. lysosomal dynein/dynactin adapter JIP4, which functionally exhibiting striking retrograde trafficking defects. Hence, our work reveals mediate mRNA, particularly along lysosomes compartments. TBCK-deficiency compartment-specific defects likely contribute preferential susceptibility neurodegeneration.

Язык: Английский

Процитировано

0
Transcriptomics in the era of long-read sequencing DOI Creative Commons
Carolina Monzó, Tianyuan Liu, Ana Conesa

и другие.

Nature Reviews Genetics, Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

Язык: Английский

Процитировано

0
Alternative Splicing in Autism Spectrum Disorder: Recent Insights from Mechanisms to Therapy DOI Creative Commons
Michael Zheng,

Nengcheng Bao,

Zhechao Wang

и другие.

Asian Journal of Psychiatry, Год журнала: 2025, Номер unknown, С. 104501 - 104501

Опубликована: Апрель 1, 2025

Alternative splicing (AS) is a vital and highly dynamic RNA regulatory mechanism that allows single gene to generate multiple mRNA protein isoforms. Dysregulation of AS has been identified as key contributor the pathogenesis autism spectrum disorders (ASD). A comprehensive understanding aberrant mechanisms their functional consequences in ASD can help uncover molecular basis disorder facilitate development therapeutic strategies. This review focuses on major events regulators associated with ASD, highlighting roles linking defective pathogenesis. In addition, discussion how emerging technologies, such long-read sequencing, single-cell spatial transcriptomics CRISPR-Cas systems are offering novel insights into role presented. Finally, splicing-based strategies evaluated, emphasizing potential address unmet clinical needs treatment.

Язык: Английский

Процитировано

0
NUAK: never underestimate a kinase DOI Creative Commons
George Skalka, Declan Whyte,

Dominika Lubawska

и другие.

Essays in Biochemistry, Год журнала: 2024, Номер unknown

Опубликована: Июнь 28, 2024

NUAK1 and NUAK2 belong to a family of kinases related the catalytic α-subunits AMP-activated protein kinase (AMPK) complexes. Despite canonical activation by tumour suppressor LKB1, both NUAKs exhibit spectrum activities that favour development progression. Here, we review similarities in structure function NUAKs, their regulation at gene, transcript level, discuss phosphorylation specific downstream targets context signal transduction pathways biological regulated each or NUAKs.

Язык: Английский

Процитировано

3
Advancing evolutionary medicine with complete primate genomes and advanced biotechnologies DOI
Kaiyue Ma, Xiangyu Yang, Yafei Mao

и другие.

Trends in Genetics, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

Процитировано

3
IsoVis – a webserver for visualization and annotation of alternative RNA isoforms DOI Creative Commons

Ching Yin Wan,

J. Davis,

Manveer Chauhan

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 52(W1), С. W341 - W347

Опубликована: Май 6, 2024

Abstract Genes commonly express multiple RNA products (RNA isoforms), which differ in exonic content and can have different functions. Making sense of the plethora known novel isoforms being identified by transcriptomic approaches requires a user-friendly way to visualize gene how they content, expression levels potential Here we introduce IsoVis, freely available webserver that accepts user-supplied data visualizes expressed clear, intuitive manner. IsoVis contains numerous features, including ability all their levels; annotation from external databases; mapping protein domains features exons, allowing changes sequence function between be established; extensive species compatibility. Datasets visualised on remain private user, analysis sensitive data. visualisations downloaded create publication-ready figures. The enables researchers perform isoform analyses without requiring programming skills, is free use, at https://isomix.org/isovis/.

Язык: Английский

Процитировано

2