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

et al.

Protein Science, Journal Year: 2024, Volume and Issue: 34(1)

Published: Dec. 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.

Language: Английский

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

et al.

Molecular Aspects of Medicine, Journal Year: 2024, Volume and Issue: 96, P. 101255 - 101255

Published: Feb. 17, 2024

Language: Английский

Citations

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

Chiara Fiorenzani,

Adele Mossa,

Silvia De Rubeis

et al.

Trends in Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

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

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 91, P. 102322 - 102322

Published: Feb. 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.

Language: Английский

Citations

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

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 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.

Language: Английский

Citations

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

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

Citations

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

et al.

Nature Reviews Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Language: Английский

Citations

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

Nengcheng Bao,

Zhechao Wang

et al.

Asian Journal of Psychiatry, Journal Year: 2025, Volume and Issue: unknown, P. 104501 - 104501

Published: April 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.

Language: Английский

Citations

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

Dominika Lubawska

et al.

Essays in Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: June 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.

Language: Английский

Citations

3
RNA structure in alternative splicing regulation: from mechanism to therapy DOI Creative Commons

Nengcheng Bao,

Zhechao Wang,

Jiayan Fu

et al.

Acta Biochimica et Biophysica Sinica, Journal Year: 2024, Volume and Issue: unknown

Published: July 1, 2024

Alternative splicing is a highly intricate process that plays crucial role in post-transcriptional regulation and significantly expands the functional proteome of limited number coding genes eukaryotes. Its multifactorial, with RNA structure exerting significant impact. Aberrant conformations lead to dysregulation patterns, which directly affects manifestation disease symptoms. In this review, molecular mechanisms secondary structure-mediated are summarized, focus on complex interplay between aberrant phenotypes resulted from defects. This study also explores additional factors reshape structural conformations, enriching our understanding mechanistic network underlying regulation. addition, an emphasis has been placed clinical targeting corrections human diseases. The principal action behind phenomenon described, followed by discussion prospective development strategies pertinent challenges.

Language: Английский

Citations

3
Long-read RNA sequencing: a transformative technology for exploring transcriptome complexity in human diseases DOI Creative Commons

Isabelle Heifetz Ament,

Nicole DeBruyne,

Feng Wang

et al.

Molecular Therapy, Journal Year: 2024, Volume and Issue: 33(3), P. 883 - 894

Published: Nov. 19, 2024

Long-read RNA sequencing (RNA-seq) is emerging as a powerful and versatile technology for studying human transcriptomes. By enabling the end-to-end of full-length transcripts, long-read RNA-seq opens up avenues investigating various species features that cannot be reliably interrogated by standard short-read methods. In this review, we present an overview RNA-seq, delineating its strengths over well summarizing recent advances in experimental computational approaches to boost power long-read-based transcriptomics. We describe wide range applications highlight expanding role foundational exploring transcriptome variations diseases.

Language: Английский

Citations

3