Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling

The EMBO Journal, Год журнала: 2025, Номер unknown

Опубликована: Апрель 22, 2025

Abstract Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα) regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). By binding to an AKAP11 scaffold, PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis. Mutations promote schizophrenia bipolar disorders (SZ-BP) through unknown mechanisms. Here, proteomic-based analyses immunopurified lysosomes, we identify Cα-RIα-AKAP11 holocomplex as prominent autophagy-associated protein-kinase complex. scaffolds Cα-RIα interaction autophagic machinery LC3-interacting region (LIR), enabling both regulation upstream signals, autophagy-dependent degradation. We Ser83 on RIα linker-hinge AKAP11-dependent phospho-residue that modulates RIα-Cα autophagosome cAMP-induced activation. Decoupling AKAP11-PKA from autophagy alters downstream phosphorylation events, supporting checkpoint signaling. Ablating induced pluripotent stem cell-derived neurons reveals dysregulation multiple pathways Thus, platform signaling, providing possible mechanistic link SZ/BP pathophysiology.

Язык: Английский

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Altered Expression of PDE4 Genes in Schizophrenia: Insights from a Brain and Blood Sample Meta-Analysis and iPSC-Derived Neurons

Genes, Год журнала: 2024, Номер 15(5), С. 609 - 609

Опубликована: Май 10, 2024

Schizophrenia symptomatology includes negative symptoms and cognitive impairment. Several studies have linked schizophrenia with the PDE4 family of enzymes due to their genetic association function in processes such as long-term potentiation. We conducted a systematic gene expression meta-analysis four genes (PDE4A-D) 10 brain sample datasets (437 samples) three blood (300 samples). Subsequently, we measured mRNA levels iPSC-derived hippocampal dentate gyrus neurons generated from fibroblasts groups: healthy controls, monozygotic twins (MZ), MZ siblings schizophrenia. found downregulation PDE4B tissues, further validated by independent data CommonMind consortium (515 Interestingly, signal was present subgroup patients, while others showed no differential or even upregulation. Notably, PDE4A, PDE4B, PDE4D exhibited upregulation compared whereas samples, be upregulated PDE4A downregulated. While precise mechanism direction altered necessitate investigation, observed multilevel across brain, blood, compellingly suggests involvement pathophysiology

Язык: Английский

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SETD1A variant-associated psychosis: A systematic review of the clinical literature and description of two new cases

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Год журнала: 2023, Номер 129, С. 110888 - 110888

Опубликована: Ноя. 1, 2023

SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding schizophrenia has achieved genome-wide significance by variant burden testing, only few studies described psychiatric phenomenology of such individuals detail. This systematic review case report aims to characterize phenotypes variant-associated schizophrenia.A PubMed search was completed July 2022 updated May 2023. Only that reported as well primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases psychosis from our own sequencing cohort are described.The yielded 32 articles. 15 articles met inclusion criteria, five provided descriptions. In total, phenotypic information available for 11 individuals, addition cases. Our findings suggest although may share number common features, variability nonetheless exists. Moreover, exhibit other features suggestive syndrome, their presentations appear be similar those general populations.Loss-of-function underlie development small percentage Identifying become increasingly important, given potential advances precision medicine treatment approaches.

Язык: Английский

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Probing the biological consequences of a previously undescribed de novo mutation of ZMYND11 in a schizophrenia patient by CRISPR genome editing and induced pluripotent stem cell based in vitro disease-modeling

Schizophrenia Research, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Schizophrenia (SCZ) is a severe neuropsychiatric disorder of complex, poorly understood etiology, associated with both genetic and environmental factors. De novo mutations (DNMs) represent new source variation in SCZ, however, most cases their biological significance remains unclear. We sought to investigate molecular disease pathways connected DNMs SCZ by combining human induced pluripotent stem cell (hiPSC) based modeling CRISPR-based genome editing. selected case-parent trio the case individual carrying potentially causing 1495C > T nonsense DNM zinc finger MYND domain-containing protein 11 (ZMYND11), gene implicated processes relevant for SCZ. In patient-derived hiPSC line mutation was corrected using CRISPR, while monoallelic or biallelic frameshift were introduced into control line. Isogenic lines differentiated hippocampal neuronal progenitor cells (NPCs) functionally active dentate gyrus granule (DGGCs). Immunofluorescence microscopy RNA sequencing used test morphological transcriptomic differences at NPC DGCC stages. Functionality neurons investigated calcium-imaging multi-electrode array measurements. Morphology mutant NPCs preserved, we detected significant functional alterations. showed massive upregulation differentiation genes, downregulation adhesion genes. Decreased reactivity glutamate demonstrated calcium-imaging. Our findings lend support involvement glutamatergic dysregulation pathogenesis This approach represents powerful model system precision psychiatry pharmacological research.

Язык: Английский

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Rare coding variants in schizophrenia-associated genes affect generalised cognition in the UK Biobank

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 16, 2023

Abstract Impairments in cognitive function are a feature of schizophrenia that strongly predict functional outcome and generally not improved by current medications. However, the nature relationship between impairment risk, particularly extent to which this reflects shared underlying biology, remains uncertain. We analysed exome-sequencing data from UK Biobank test for association generalised cognition damaging rare coding variation genes loci associated with 30,487 people without disorder. Rare protein-truncating variants (PTVs) missense loss-of-function intolerant (LoFi) were lower cognition. Moreover, we found significantly stronger effects credible causal at GWAS PTVs affecting LoFi regions defined schizophrenia-enriched CNVs. This suggests biology risk general population, exploiting large population sequencing datasets identify on can provide route towards determining biological processes schizophrenia.

Язык: Английский

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What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?

Journal of Translational Genetics and Genomics, Год журнала: 2024, Номер 8(1), С. 1 - 12

Опубликована: Янв. 11, 2024

With a population prevalence of 1%, schizophrenia is widespread, yet the aetiology this psychiatric disorder remains elusive. There an evident genetic component schizophrenia, with heritability estimates lying at 60%-80%. While genome-wide association studies have identified 120 gene loci associated risk, these involved common variants that confer only small effects on individual risk (median odds ratio < 1.2). The recent emergence whole exome sequencing (WES) technologies has facilitated identification rare sequence variants, including some protein-truncating significant risk. Three key large-scale WES demonstrated in genes SETD1A , CACNA1G CUL1 GRIA3 GRIN2A HERC1 RB1CC1 SP4 TRIO XPO7 and AKAP11 substantial for schizophrenia. These are highly expressed central nervous system neurons their products participate diverse molecular functions synaptic transmission, transcriptional regulation, ubiquitin ligation. understanding functional roles illuminates putative mechanisms which may lead to schizophrenia-like phenotypes. It will also be possible develop model systems impaired function can further explored. Genetic date suggest glutamatergic dysregulation, chromatin modification, ubiquitin-proteasome play aetiology.

Язык: Английский

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A preliminary metabolomics study of the database for biological samples of schizophrenia among Chinese ethnic minorities

BMC Psychiatry, Год журнала: 2024, Номер 24(1)

Опубликована: Апрель 9, 2024

Abstract Background Schizophrenia (SCZ) is a profound mental disorder with multifactorial etiology, including genetics, environmental factors, and demographic influences such as ethnicity geography. Among these, the studies of SCZ also shows racial regional differences. Methods We first established database biological samples for in China’s ethnic minorities, followed by serum metabolomic analysis patients from various groups within same region using LC-HRMS platform. Results Analysis identified 47 metabolites associated SCZ, 46 showing significant differences between Miao Han patients. These metabolites, primarily fatty acids, amino benzene, derivatives, are involved acid metabolism pathways. Notably, L-Carnitine, L-Cystine, Aspartylphenylalanine, Methionine sulfoxide demonstrated greater diagnostic efficacy compared to Conclusion Preliminary findings suggest that there metabolic levels among different ethnicities region, offering insights developing objective or therapeutic monitoring strategies incorporate considerations SCZ.

Язык: Английский

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Prioritizing disease-related rare variants by integrating gene expression data

PLoS Genetics, Год журнала: 2024, Номер 20(9), С. e1011412 - e1011412

Опубликована: Сен. 30, 2024

Rare variants, comprising the vast majority of human genetic variations, are likely to have more deleterious impact in context diseases compared common variants. Here we present carrier statistic, a statistical framework prioritize disease-related rare variants by integrating gene expression data. By quantifying on expression, statistic can those that large functional consequence patients. Through simulation studies and analyzing real multi-omics dataset, demonstrated is applicable with limited sample size (a few hundreds) achieves substantially higher sensitivity than existing association methods. Application Alzheimer’s disease reveals 16 within 15 genes extreme statistics. We also found strong excess among top prioritized patients healthy individuals. The method be applied various variant types adaptable other omics data modalities, offering powerful tool for investigating molecular mechanisms underlying complex diseases.

Язык: Английский

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Reduction of SynGAP-γ, disrupted splicing ofAgap3, and oligodendrocyte deficits inSrrm2mice, a genetic model of schizophrenia and neurodevelopmental disorder

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 12, 2024

Abstract Rare loss-of-function (LoF) variants in SRRM2 , which encodes the splicing factor, are associated with schizophrenia and a neurodevelopmental disorder. How haploinsufficiency of leads to brain dysfunction is unknown. We find that Srrm2 +/- mice display (i) large-scale changes gene expression neuronal glial cells, affecting synapse-related other common molecular pathways across multiple regions, (ii) reduction key postsynaptic proteins, including gamma isoform SynGAP, itself encoded by disorder risk gene, (iii) abnormal elevated Agap3, SynGAP interactor, (iv) reduced numbers oligodendrocytes accompanied decreased myelin-related mRNAs (v) behavioral EEG abnormalities, sleep spindles phenocopy humans schizophrenia. Our findings provide insights into neurobiological mechanisms potential therapeutic avenues for LoF

Язык: Английский

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Analysis of exome sequencing data implicates rare coding variants in STAG1 and ZNF136 in schizophrenia

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 16, 2024

Abstract Rare coding variants across many genes contribute to schizophrenia liability, but they have only been implicated in 12 at exome-wide levels of significance. To increase power for gene discovery, we analysed exome-sequencing data rare a new sample 4,650 cases and 5,719 controls, combined these with published sequencing total 28,898 cases, 103,041 controls 3,444 proband-parent trios. Novel associations were identified STAG1 ZNF136 significance six additional false discovery rate 5%. Among genes, SLC6A1 KLC1 are associated damaging missense alone. Four the eight novel also enriched other developmental psychiatric disorders. Moreover, fine-mapped common variant signals schizophrenia. These findings provide insights into neurobiology schizophrenia, including an aetiological role disrupted chromatin organisation.

Язык: Английский

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