CTNNB1 in neurodevelopmental disorders

Zhuang, Wenting; Ye, Tong; Wang, Wei; Song, Weihong; Tan, Tao

doi:10.3389/fpsyt.2023.1143328

Cited by 11 publications

(9 citation statements)

References 92 publications

(108 reference statements)

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“…MYC is at the crossroads of multiple signaling pathways, including WNT signaling [58], and its increased expression leads to elevated vulnerability of neurons in degenerative diseases [74]. CTNNB1 is a key player in the WNT signaling pathway [57]. In concordance with the literature, we observed increased expression of MYC and CTNNB1, increased repressor TF activity for both, and overall decreased WNT signaling in AD.…”

Section: Discussionsupporting

confidence: 89%

Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

Soelter,

Howton,

Clark

et al. 2023

Preprint

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BackgroundAlzheimer’s disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer’s disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer’s disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons.MethodsUsing public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in an independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons.ResultsCell-cell communication between glia and neurons is altered in Alzheimer’s disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We validated 51 ligand- receptor pairs in an independent dataset that included two known Alzheimer’s disease risk genes:APPandAPOE. 17 (14 upregulated and 3 downregulated in Alzheimer’s disease) of the 51 interactions also had the same downstream target gene. Most of the signaling mediators of these interactions were not differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely,MYCandTP53, which are associated with WNT and p53 signaling, respectively, had repressor activity in Alzheimer’s disease, along with decreased WNT and p53 activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and activator activity ofNFIL3, an NFkB signaling-associated transcription factor.ConclusionsCell-cell communication between glia and neurons in Alzheimer’s disease is altered in a cell-type-specific manner involving Alzheimer’s disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.

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Section: Discussionsupporting

confidence: 89%

Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

Soelter,

Howton,

Clark

et al. 2023

Preprint

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“…3h and 15 Mb in chromosome X in Fig. 3h ) containing genes involved in neurodevelopment 35,36 , such as GALNT2 , MECP2, and CTNNB1 , in probands with NN disorders ( Extended Data Fig. 4a ).…”

Section: Resultsmentioning

confidence: 99%

Deciphering the role of germline complex de novo structural variations in rare disorders

Jung,

Yang,

Walker

et al. 2024

Preprint

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De novo structural variants (dnSVs) have emerged as crucial genetic factors in the context of rare disorders. However, these variations often go undiagnosed in routine genetic screening practices. To shed light on their significance in rare disease, we conducted a comprehensive analysis of the largest cohort of parent-offspring whole-genome sequencing data from the UK 100,000 Genomes Project. Our study encompassed a vast cohort of 12,568 families, including 13,702 offspring affected by rare genetic diseases. We identified a total of 1,872 dnSVs, revealing that approximately 12% of the probands harboured at least one dnSV, of which 9% were identified as likely pathogenic in affected probands (151/1696). Advanced parents' age was found to be associated with an increased chance of having dnSVs in probands. We discovered 148 clustered breakpoints resulting from a single event. 60% of these complex dnSVs were classified into 9 major SV types, and could be observed in multiple individuals, while the remaining 40% were private events and had not been previously reported. We found 12% of pathogenic dnSVs are complex SVs, emphasising the critical importance of thoroughly examining and considering complex dnSVs in the context of rare disorders. Furthermore, we discovered an enrichment of maternal dnSVs at subtelometric, early-replicating regions of chromosome 16, suggesting possible sex-specific mechanisms in generation of dnSVs. This study sheds light on the extent of diversity of dnSVs in the germline and their contribution to rare genetic disorders.

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“…Nonetheless, our findings on macular thinning could potentially reflect Wnt dysregulation which can lead to deleterious effects in neuronal development, contributing to the pathogenesis of neurodevelopmental diseases like schizophrenia. 19,50 Other Wnt signaling pathways also play a significant role in the protection of damaged retinal neurons. 51 They have been shown to have a significant impact on retinal vessel formation and maturation, as well as on the establishment of synaptic structures and neuronal function in the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank

Rabe,

Smigielski,

Georgiadis

et al. 2024

Preprint

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The human retina is part of the central nervous system and can be easily and non- invasively imaged through optical coherence tomography. Imaging the retina may provide insights on central nervous system related disorders such as schizophrenia. Here, our objective was to investigate if variations in retinal phenotypes could be at- tributed to common genetic variations conveying a risk of schizophrenia as measured by polygenic risk scores. We used population data from the UK Biobank, including White British and Irish individuals without diagnosed schizoprenia, and estimated a polygenic risk score for schizophrenia based on the newest genome-wide association study (PGC release 2022). We hypothesized that greater genetic susceptibility to schizophrenia is associated with retinal thinning, especially within the macula. To gain additional mechanistic insights, we conducted pathway-specific polygenic risk score associations analyses, focusing on gene pathways that are related to schizophrenia. Of 65484 individuals recruited, 48208 participants with available matching imaging- genetic data were included in the analysis of whom 22427 (53.48%) were female and 25781 (46.52%) were male. 5148 individuals were excluded on the basis of incomplete optical coherence tomog- raphy data (for all phenotypes), 198 individuals based on the use of antipsychotics and 197 individuals with schizophrenia, schizotypal- and delusional disorders. Our robust principal component regression results showed that polygenic risk scores for schizophrenia were associated with retinal thinning while controlling for confounding factors (b = -0.03, p = 0.007). Similarly, we found that polygenic risk for schizophrenia specific to neuroinflammation gene sets revealed significant associations with retinal thinning (b = -0.03, self-contained p = 0.041 (reflecting the level of association), com- petitive p = 0.05 (reflecting the level of enrichment)). These results go beyond previ- ous studies suggesting a relationship between manifested schizophrenia and retinal phenotypes. They indicate that the retina is a mirror reflecting the genetic complex- ities of schizophrenia. These associations also suggest the potential involvement of the neuroinflammatory pathway, with indications of genetic overlap in certain retinal phenotypes. The findings further indicate that this gene pathway in individuals with a high polygenic risk for schizophrenia could contribute through acute-phase proteins to structural changes in the retina.

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CTNNB1 in neurodevelopmental disorders

Cited by 11 publications

References 92 publications

Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

Deciphering the role of germline complex de novo structural variations in rare disorders

Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank

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