Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

Rossi, Joseph J; Rosenfeld, Jill A.; Chan, Katie; Streff, Haley; Nankivell, Victoria; Peet, Daniel J.; Whitelaw, Murray L.; Bersten, David C.

doi:10.1038/s41598-021-86041-4

Cited by 12 publications

(5 citation statements)

References 73 publications

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, a frameshift mutation in NPAS3 has recently been reported at amino acid 214 in an individual with intellectual disability [48]. This mutation impairs the activity of NPAS3, and the mutant form is expressed at a lower level than the full-length protein (likely as a result of reduced stability) in human cultured cells [48]. The frameshift protein would be very close in length to the mislocalizing and aggregation-prone aa 1-208 fragment expressed in this study, indicating new mechanisms through which this mutation could cause disruption.…”

Section: Discussionmentioning

confidence: 99%

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Protein Aggregation of NPAS3, Implicated in Mental Illness, Is Not Limited to the V304I Mutation

Samardžija

Radonja

Zaharija

et al. 2021

JPM

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An emerging phenomenon in our understanding of the pathophysiology of mental illness is the idea that specific proteins may form insoluble aggregates in the brains of patients, in partial analogy to similar proteinopathies in neurodegenerative diseases. Several proteins have now been detected as forming such aggregates in the brains of patients, including DISC1, dysbindin-1 and TRIOBP-1. Recently, neuronal PAS domain protein 3 (NPAS3), a known genetic risk factor for schizophrenia, was implicated through a V304I point mutation in a family with major mental illness. Investigation of the mutation revealed that it may lead to aggregation of NPAS3. Here we investigated NPAS3 aggregation in insular cortex samples from 40 individuals, by purifying the insoluble fraction of these samples and testing them by Western blotting. Strikingly, full-length NPAS3 was found in the insoluble fraction of 70% of these samples, implying that aggregation is far more widely spread than can be accounted for by this rare mutation. We investigated the possible mechanism of aggregation further in neuroblastoma cells, finding that oxidative stress plays a larger role than the V304I mutation. Finally, we tested to see if NPAS3 aggregation could also be seen in blood serum, as a more accessible tissue than the human brain for future diagnosis. While no indication of NPAS3 aggregation was seen in the serum, soluble NPAS3 was detected, and was more prevalent in patients with schizophrenia than in those with major depressive disorder or controls. Aggregation of NPAS3 therefore appears to be a widespread and multifactorial phenomenon. Further research is now needed to determine whether it is specifically enhanced in schizophrenia or other mental illnesses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protein Aggregation of NPAS3, Implicated in Mental Illness, Is Not Limited to the V304I Mutation

Samardžija

Radonja

Zaharija

et al. 2021

JPM

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“…As one example, bulk RNA-seq identified the upregulation of NPAS3 in SCZ (logFC = 0.14, p = 5.5 × 10 −4 ), a change that was uniquely observed in SST cells in our analyses (logFC = 0.36, p = 7.4 × 10 −6 ). NPAS3 plays a broad role in neurogenesis, and mutations in this gene have been associated with SCZ and neurodevelopmental disorders (59,60). LCM-seq cell-specific disease signatures were also moderately consistent with those surveyed in recent human snRNA-seq datasets from MDD and SCZ (30,34), as assessed by rank-rank hypergeometric overlap analysis ( Supplemental Figure 4 , see Methods).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic pathology of neocortical microcircuit cell types across psychiatric disorders

Arbabi,

Newton,

et al. 2023

Preprint

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Background: Psychiatric disorders like major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are characterized by altered cognition and mood, brain functions that depend on information processing by cortical microcircuits. We hypothesized that psychiatric disorders would display cell type-specific transcriptional alterations in neuronal subpopulations that make up cortical microcircuits: excitatory pyramidal (PYR) neurons and vasoactive intestinal peptide- (VIP), somatostatin- (SST), and parvalbumin- (PVALB) expressing inhibitory interneurons. Methods: We performed cell type-specific molecular profiling of subgenual anterior cingulate cortex, a region implicated in mood and cognitive control, using laser capture microdissection followed by RNA sequencing (LCM-seq). We sequenced libraries from 130 whole cells pooled per neuronal subtype (VIP, SST, PVALB, superficial and deep PYR) in 76 subjects from the University of Pittsburgh Brain Tissue Donation Program, evenly split between MDD, BD and SCZ subjects and healthy controls. Results: We identified hundreds of differentially expressed (DE) genes and biological pathways across disorders and neuronal subtypes, with the vast majority in inhibitory neuron types, particularly PVALB. DE genes were distinct across cell types, but partially shared across disorders, with nearly all shared genes involved in the formation and maintenance of neuronal circuits. Coordinated alterations in biological pathways were observed between select pairs of microcircuit cell types and partially shared across disorders. Finally, DE genes coincided with known risk variants from psychiatric genome-wide association studies, indicating cell type-specific convergence between genetic and transcriptomic risk for psychiatric disorders. Conclusions: We present the first cell type-specific dataset of cortical microcircuit gene expression across multiple psychiatric disorders. Each neuronal subtype displayed unique dysregulation signatures, some shared across cell types and disorders. Inhibitory interneurons showed more dysregulation than excitatory pyramidal neurons. Our study suggests transdiagnostic cortical microcircuit pathology in SCZ, BD, and MDD and sets the stage for larger-scale studies investigating how cell circuit-based changes contribute to shared psychiatric risk.

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“…Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified alterations in inflammatory IL17 pathway and amphetamine addiction (Figure 2C). Among the corticosterone pathways genes were Th 39 , Trh 40 and Npas [41][42][43][44] .…”

Section: Cerebellar Expression Of Mutant Atxn1 Is Sufficient To Impac...mentioning

confidence: 99%

Cerebellar contribution to cognitive deficits and prefrontal cortex dysfunction in Spinocerebellar Ataxia Type 1 (SCA1)

Sbrocco,

Borgenheimer,

Zhang

et al. 2024

Preprint

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The cerebellum role in cognition and its functional bi-directional connectivity with prefrontal cortex (PFC) is well recognized. However, how chronic cerebellar dysfunction affects PFC function and cognition remains less understood. Spinocerebellar ataxia type 1 (SCA1), is an inherited, fatal neurodegenerative disease caused by an abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1) and characterized by severe loss of Purkinje cells (PCs) in the cerebellum. Patients with SCA1 suffer from movement and balance deficits, cognitive decline and premature lethality. Cognitive deficits significantly impact patients quality of life, yet how exactly cerebellar degeneration contributes to cognitive deficits and PFC dysfunction in SCA1 is unknown. We have previously demonstrated that expression of mutant ATXN1 only in cerebellar Purkinje cells (PCs) is sufficient to cause cognitive deficits in a transgenic ATXN1[82Q] mouse line. To understand how cerebellar dysfunction impacts the PFC, we examined neuronal activity, synaptic density, and gene expression changes in the PFC of ATXN1[82Q] mice. Remarkably, we found decreased neuronal activity, reduced synaptic density, and altered expression of immediate early genes and pathways involved in glucose metabolism, inflammation and amphetamine in the PFC of ATXN1[82Q] mice. Furthermore, we characterized cellular and molecular PFC dysfunction in a novel conditional knock-in SCA1 line, f-ATXN1146Q mice, expressing floxed human expanded ATXN1 throughout the brain. Intriguingly, we found an increased number of neurons, increased synaptic density and large gene expression alterations in the PFC of f-ATXN1146Q mice. Finally, to precisely determine the role of cerebellar dysfunction in cognitive deficits and PFC dysfunction in SCA1, we crossed f-ATXN1146Q mice with Pcp2-Cre mice expressing Cre recombinase in PCs to delete expanded ATXN1 only in PCs. Surprisingly, we have found that deleting expanded ATXN1 in PCs exacerbated cognitive deficits and PFC dysfunction in these mice. Our findings demonstrate that circumscribed cerebellar dysfunction is sufficient to impact PFC activity and synaptic connectivity impairing cognition. However, when multiple brain regions are impacted in disease, cerebellar dysfunction may ameliorate PFC pathology and cognitive performance.

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Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

Cited by 12 publications

References 73 publications

Protein Aggregation of NPAS3, Implicated in Mental Illness, Is Not Limited to the V304I Mutation

Protein Aggregation of NPAS3, Implicated in Mental Illness, Is Not Limited to the V304I Mutation

Transcriptomic pathology of neocortical microcircuit cell types across psychiatric disorders

Cerebellar contribution to cognitive deficits and prefrontal cortex dysfunction in Spinocerebellar Ataxia Type 1 (SCA1)

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