Deep proteomics identifies shared molecular pathway alterations in synapses of patients with schizophrenia and bipolar disorder and mouse model

Aryal, Sameer; Bonanno, Kevin; Song, Bryan; Mani, D. R.; Keshishian, Hasmik; Carr, Steven A.; Sheng, Morgan; Dejanovic, Borislav

doi:10.1016/j.celrep.2023.112497

Cited by 13 publications

(8 citation statements)

References 86 publications

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“…Consistent with previous research providing evidence of downregulated mitochondrial ribosomal subunit genes in the brain and blood samples of SCZ patients 88 as well as decreased synaptic mitochondrial content and ribosomal proteins in patients with BD, SCZ, and AKAP11 -mutant mice 34 , we detected significant downregulation of ribosomal protein genes and mitochondrial ribosomal protein genes along with other regulators involved in protein synthesis in our model. One possible explanation for the decreased expression of ribosomal proteins following heterozygous KO of AKAP11 could be the inhibition of mTORC1 upon modifications in the upstream signals including growth factors, stress, or energy status 89 .…”

Section: Discussionsupporting

confidence: 92%

“…A study looking at AKAP11 mutant mice found that their EEG patterns resembled those observed in individuals with SCZ 31 . In another study, proteomic profiling of synapses found shared molecular pathway modifications between patients with SCZ, BD, and AKAP11 -mutant mouse models--mainly pathways related to ribosomes, mitochondrial respiration, and vesicle trafficking pathways 34 . Our study, for the first time, uncovers the transcriptomic and epigenomic consequences of heterozygous LoF mutations in AKAP11 , a novel rare-variant large-effect risk gene for BD and SCZ, in the context of human iPSC-derived neurons.…”

Section: Discussionmentioning

confidence: 95%

“…electroencephalography (EEG) phenotypes similar to those observed in human SCZ patients were detected 31-33 . Another study carried out a deep proteomics analysis of synapses in Akap11 -mutant mice and detected some overlap between the dysregulated pathways in SCZ and BD patients and the mutant model 34 . However, our study is the first to investigate the effect of heterozygous LoF mutations in AKAP11 at the transcriptomic and epigenetic (DNA methylation and histone modification) levels in a human cellular model.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic and epigenomic consequences of heterozygous loss of function mutations inAKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia

Farhangdoost,

Liao,

Liu

et al. 2024

Preprint

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The gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile of Akap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout of AKAP11, particularly in human neurons. In this study, we use genome-wide approaches to investigate such aberrations in human induced pluripotent stem cell (iPSC)-derived neurons. We show the impact of heterozygous AKAP11 LoF mutations on the gene expression landscape and profile the methylomic and acetylomic modifications. Altogether we highlight the involvement of aberrant activity of intergenic and intronic enhancers, which are enriched in PBX homeobox 2 (PBX2) and Nuclear Factor-1 (NF1) known binding motifs, respectively, in transcription dysregulations of genes functioning as DNA-binding transcription factors, actin and cytoskeleton regulators, and cytokine receptors, as well as genes involved in G-protein-coupled receptors (GPCRs) binding and signaling. A better understanding of the dysregulations resulting from haploinsufficiency in AKAP11 improves our knowledge of the biological roots and pathophysiology of BD and SCZ, paving the way for better therapeutic approaches.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Transcriptomic and epigenomic consequences of heterozygous loss of function mutations inAKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia

Farhangdoost,

Liao,

Liu

et al. 2024

Preprint

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“…Additionally, reduced levels of NPTX2 in the CSF have been observed in individuals with recent-onset schizophrenia, and its concentration correlates with cognitive performance (Xiao et al 2021). Biochemical analysis of schizophrenia and bipolar disorder patient tissues also revealed reduced levels of NPTX2 in synaptosome fraction (Aryal et al 2023). Importantly, sleep is disrupted to various degrees in each of these conditions.…”

Section: Introductionmentioning

confidence: 99%

Sleep and circadian rhythm disruption by NPTX2 loss of function

Roh,

Xiao,

Delgado

et al. 2023

Preprint

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Sleep and circadian rhythm disruption (SCRD) is commonly observed in aging, especially in individuals who experience progressive cognitive decline to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, precise molecular mechanisms underlying the association between SCRD and aging are not fully understood. Orexin A is a well-characterized “sleep neuropeptide” that is expressed in hypothalamic neurons and evokes wake behavior. The importance of Orexin is exemplified in narcolepsy where it is profoundly down-regulated. Interestingly, the synaptic immediate early gene NPTX2 is co-expressed in Orexin neurons and is similarly reduced in narcolepsy. NPTX2 is also down-regulated in CSF of some cognitively normal older individuals and predicts the time of transition from normal cognition to MCI. The association between Orexin and NPTX2 is further evinced here where we observe that Orexin A and NPTX2 are highly correlated in CSF of cognitively normal aged individuals and raises the question of whether SCRD that are typically attributed to Orexin A loss of function may be modified by concomitant NPTX2 down-regulation. Is NPTX2 an effector of sleep or simply a reporter of orexin-dependent SCRD? To address this question, we examined NPTX2 KO mice and found they retain Orexin expression in the brain and so provide an opportunity to examine the specific contribution of NPTX2 to SCRD. Our results reveal that NPTX2 KO mice exhibit a disrupted circadian onset time, coupled with increased activity during the sleep phase, suggesting difficulties in maintaining states. Sleep EEG indicates distinct temporal allocation shifts across vigilance states, characterized by reduced wake and increased NREM time. Evident sleep fragmentation manifests through alterations of event occurrences during Wake and NREM, notably during light transition periods, in conjunction with an increased frequency of sleep transitions in NPTX2 KO mice, particularly between Wake and NREM. EEG spectral analysis indicated significant shifts in power across various frequency bands in the wake, NREM, and REM states, suggestive of disrupted neuronal synchronicity. An intriguing observation is the diminished occurrence of sleep spindles, one of the earliest measures of human sleep disruption, in NPTX2 KO mice. These findings highlight the effector role of NPTX2 loss of function as an instigator of SCRD and a potential mediator of sleep disruption in aging.

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“…Psychosis has been associated with specific neurobiological alterations, such as neurotransmitters 9,10 , metabolism 11 , cell type 12,13 , and microstructure 14 . Studies on prevalent genetic variations linked to SCZ have consistently pointed towards synaptic function as key factor in terms of disease risk 15 . Specifically, dysregulation of dopaminergic neurotransmission has been detected in SCZ 16 , and several neurochemical systems have been suggested to contribute to psychosis pathophysiology, including the glutamate, gamma-aminobutyric acid (GABA), serotonin, and acetylcholine neurotransmitters 9,17 .…”

Section: Introductionmentioning

confidence: 99%

Molecular and micro-architectural mapping of gray matter alterations in psychosis

Garcia-San-Martin,

Bethlehem,

Mihalik

et al. 2023

Preprint

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The psychosis spectrum encompasses a heterogeneous range of clinical conditions associated with abnormal brain development. The molecular and micro-architectural attributes that account for structural deviations from typical neurodevelopment are still unknown. Here, we aggregate magnetic resonance imaging data from 38,696 healthy controls and 1,256 psychosis-related cases, including first-degree relatives, psychotic experiences, first-episodes, and chronic conditions. Using normative modeling, we generated centile scores for cortical gray matter phenotypes, identifying deviations in regional volumes below the expected trajectory for all conditions. Additionally, we mapped 46 neurobiological features from healthy individuals (including neurotransmitters, cell types, layer thickness, microstructure, cortical expansion, and metabolism) to these centiles using a multivariate approach. Results revealed that neurobiological features were highly co-localized with centile deviations, where metabolism and neurotransmitter concentrations showed the most consistent spatial overlap with abnormal developmental trajectories. These findings shed light on the vulnerability factors that may underlie atypical brain maturation during different stages of psychosis.

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Deep proteomics identifies shared molecular pathway alterations in synapses of patients with schizophrenia and bipolar disorder and mouse model

Cited by 13 publications

References 86 publications

Transcriptomic and epigenomic consequences of heterozygous loss of function mutations inAKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia

Transcriptomic and epigenomic consequences of heterozygous loss of function mutations inAKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia

Sleep and circadian rhythm disruption by NPTX2 loss of function

Molecular and micro-architectural mapping of gray matter alterations in psychosis

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