Molecular Psychiatry最新文献

{"title":"Circular RNAs in neurological conditions – computational identification, functional validation, and potential clinical applications","authors":"Oak Hatzimanolis, Alex M. Sykes, Alexandre S. Cristino","doi":"10.1038/s41380-025-02925-1","DOIUrl":"10.1038/s41380-025-02925-1","url":null,"abstract":"Non-coding RNAs (ncRNAs) have gained significant attention in recent years due to advancements in biotechnology, particularly high-throughput total RNA sequencing. These developments have led to new understandings of non-coding biology, revealing that approximately 80% of non-coding regions in the genome possesses biochemical functionality. Among ncRNAs, circular RNAs (circRNAs), first identified in 1976, have emerged as a prominent research field. CircRNAs are abundant in most human cell types, evolutionary conserved, highly stable, and formed by back-splicing events which generate covalently closed ends. Notably, circRNAs exhibit high expression levels in neural tissue and perform diverse biochemical functions, including acting as molecular sponges for microRNAs, interacting with RNA-binding proteins to regulate their availability and activity, modulating transcription and splicing, and even translating into functional peptides in some cases. Recent advancements in computational and experimental methods have enhanced our ability to identify and validate circRNAs, providing valuable insights into their biological roles. This review focuses on recent developments in circRNA research as they related to neuropsychiatric and neurodegenerative conditions. We also explore their potential applications in clinical diagnostics, therapeutics, and future research directions. CircRNAs remain a relatively underexplored area of non-coding biology, particularly in the context of neurological disorders. However, emerging evidence supports their role as critical players in the etiology and molecular mechanisms of conditions such as schizophrenia, bipolar disorder, major depressive disorder, Alzheimer’s disease, and Parkinson’s disease. These findings suggest that circRNAs may provide a novel framework contributing to the molecular dysfunctions underpinning these complex neurological conditions.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"30 4","pages":"1652-1675"},"PeriodicalIF":9.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41380-025-02925-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examination of mitochondria- and inflammasome-mediated mechanisms of clozapine-induced myocarditis using patient-derived iPSC cardiomyocytes","authors":"Nazanin Vaziri, Timothy E. Shutt, Wasi Karim, Thomas J. Raedler, Christos Pantelis, Naveen Thomas, Mahesh Jayaram, Steven C. Greenway, Chad A. Bousman","doi":"10.1038/s41380-025-02935-z","DOIUrl":"https://doi.org/10.1038/s41380-025-02935-z","url":null,"abstract":"<p>Clozapine is the only approved pharmacotherapy for treatment-resistant schizophrenia. However, widespread utilization of clozapine is constrained due to the potential for severe adverse effects, including myocarditis. Multiple mechanisms have been suggested to account for the cardiotoxic effects of clozapine, yet these investigations have not used cells derived from clozapine treated patients. In this study, cardiomyocytes that were derived from induced pluripotent stem cells generated from four patients with treatment-resistant schizophrenia with (<i>n</i> = 2) and without (<i>n</i> = 2) a history of clozapine-induced myocarditis were used to assess mitochondria- and NLRP3 inflammasome-mediated mechanisms of this severe adverse drug reaction. We found treatment of cardiomyocytes with a physiologically-relevant dose (2.8 µM) of clozapine for 24 h: (1) induced cardiac dysfunction, increased cytotoxicity, and apoptosis, (2) induced oxidative stress by elevating the level of reactive oxygen species and mitochondrial fragmentation, and (3) elevated levels of proinflammatory cytokines and activated the NLRP3 inflammasome. These effects were more pronounced in cardiomyocytes derived from individuals with a history of clozapine-induced myocarditis. Furthermore, pharmacological targeting of the mitochondria (elamipretide) and inflammasome (ustekinumab) attenuated these clozapine-induced cardiotoxic effects. Collectively, these results suggest a mitochondria- and NLRP3 inflammasome-mediated mechanism in the development of myocarditis associated with clozapine and support further evaluation of therapeutics that target mitochondria and NLRP3 signaling.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"49 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transthyretin, a novel prognostic marker of POCD revealed by time-series RNA-sequencing analysis","authors":"Xiaosheng Liang, Chao Song, Jingrun Lin, Shufang Li, Linpeng Li, Guoku Dai, Ruohui Zhang, Olivia Meilan Zou, Hongyu Yao, Libing Zhou, Yi Zou","doi":"10.1038/s41380-025-02918-0","DOIUrl":"https://doi.org/10.1038/s41380-025-02918-0","url":null,"abstract":"<p>Postoperative cognitive dysfunction (POCD) is defined as a declined cognition, measured by neuropsychological tests, that persists for months or even longer after surgery. Heterogeneities in the diagnosis of POCD usually involve differences in the test batteries, the cutoffs, and the timing of assessments. Although peripheral and CSF markers of neuroinflammation have been shown to correlate with increased risk of POCD, most of them are non-specific and cannot be used for POCD diagnosis. These factors hampered the understanding of the pathogenesis of POCD as well as the development of effective preventions/treatments. In this study, we found Ttr in a panel of potential POCD biomarkers identified using time-series analysis of the transcriptomes and proteomes of the hippocampi of POCD mice that diagnosed on individual basis with composite Z-scores of test batteries consisting of Y maze and open field test. Compared with their counterparts without POCD, the levels of Ttr were significantly lower in the peripheral circulation as well as in the hippocampi of the mice developed POCD at all indicated time points after surgery. The levels of peripheral TTR in human patients with delayed neurocognitive recovery were found to be reduced at 24 h after abdominal surgery, compared with those who did not. Endogenous expression of Ttr was verified in microglia cells both in vitro and in vivo. Results of in vitro assay indicated a potential role of Ttr in ameliorating LPS-induced microglial priming and protecting the differentiation of oligodendrocyte progenitor cells (OPCs) in proinflammatory microenvironment, which was one of the determinant factors in regulating the pathological progression of POCD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"184 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal evidence of mediodorsal thalamus-prefrontal circuit dysfunctions in clinical high-risk for psychosis: findings from a combined 7T fMRI, MRSI and sleep Hd-EEG study","authors":"Ahmadreza Keihani, Francesco L. Donati, Sabine A. Janssen, Chloe A. Huston, Chan-Hong Moon, Hoby P. Hetherington, James D. Wilson, Ahmad Mayeli, Fabio Ferrarelli","doi":"10.1038/s41380-025-02924-2","DOIUrl":"https://doi.org/10.1038/s41380-025-02924-2","url":null,"abstract":"<p>Deficits in mediodorsal thalamus-dorsolateral prefrontal cortex (MDT-DLPFC) resting-state functional magnetic resonance imaging (rs-fMRI) connectivity and prefrontal sleep spindles have been reported in chronic and early course schizophrenia. However, the presence of these alterations in clinical high-risk for psychosis (CHR), alongside their relationships with underlying neurotransmission and cognitive function, remains to be established. Thirty-one CHR and thirty-two HC underwent: 1) 7 T rs-fMRI; 2) 7 T magnetic resonance spectroscopy imaging (MRSI); and 3) sleep electroencephalography (EEG). Rs-fMRI connectivity was analyzed by seeding the whole thalamus (WT) and seven thalamic subsections. Spindle duration was computed across all EEG channels. GABA/creatine (Cr) and glutamate/Cr were calculated in DLPFC and MDT. Relative to HC, CHR showed WT-DLPFC hypoconnectivity (p-FDR = 0.001), especially involving MDT-DLPFC (p-FDR &lt; 0.001) and reduced prefrontal spindle duration (t-stat = −2.64, <i>p</i> = 0.010), while no differences were found for MRSI neuro-metabolites. We then performed clustering analysis using rs-fMRI connectivity and spindle duration to identify CHR and HC subgroups and predict their working memory (WM) performance. A cluster with intact rs-fMRI and spindle duration included mostly HC (83.33% purity), while a cluster with both measures altered involved almost entirely CHR (91.66% purity) and showed worse WM performances. We also examined MRSI metabolites’ contribution to spindles and rs-fMRI connectivity with a within-group multivariable regression analysis. In HC, but not in CHR, MDT glutamate/Cr negatively predicted spindle duration and positively predicted MDT-DLPFC connectivity. Combined, these findings indicate that a multimodal neuroimaging approach can identify distinct thalamocortical dysfunctions in CHR individuals, thus informing future research aimed at developing personalized interventions in these individuals.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"208 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing metabolomic and proteomic changes in depression: a systematic analysis","authors":"Juncai Pu, Yiyun Liu, Hailin Wu, Chi Liu, Yin Chen, Wei Tang, Yue Yu, Siwen Gui, Xiaogang Zhong, Dongfang Wang, Xiaopeng Chen, Yue Chen, Xiang Chen, Renjie Qiao, Yanyi Jiang, Hanping Zhang, Yi Ren, Li Fan, Haiyang Wang, Peng Xie","doi":"10.1038/s41380-025-02919-z","DOIUrl":"https://doi.org/10.1038/s41380-025-02919-z","url":null,"abstract":"<p>Despite the widespread use of metabolomics and proteomics to explore the molecular landscape of depression, there is a lack of consensus regarding dysregulated molecules with replicable evidence. Thus, this study aimed to identify robust metabolomic and proteomic features in depression by integrating evidence from large-scale studies. In this study, a knowledge base-mining approach was adopted to compile a list of dysregulated molecules derived from metabolomic and proteomic studies. A vote-counting approach was performed to identify consistently altered molecules in the blood and urine samples of patients with depression. A total of 2398 molecular entries were selected, comprising 857 unique metabolites and 468 unique proteins from 143 metabolomic and 23 proteomic studies in depression. The results of vote-counting analyses revealed that 11 metabolites in blood and 5 metabolites in urine exhibited consistent disturbances across studies. Circulating levels of glutamic acid and phosphatidylcholine (32:0) were elevated in depressive patients, whereas the levels of tryptophan, kynurenic acid, kynurenine, acetylcarnitine, serotonin, creatinine, inosine, phenylalanine, and valine were lower. Urinary levels of isobutyric acid, alanine, and nicotinic acid were higher, whereas the levels of N-methylnicotinamide and tyrosine were lower. Moreover, analysis of the proteomic dataset identified only one circulating protein, ceruloplasmin, that was consistently dysregulated. Convergence comparison prioritized tryptophan as the top-ranked circulating metabolite, followed by kynurenic acid, acetylcarnitine, creatinine, serotonin, and valine. Collectively, robust evidence of metabolomic changes was observed in patients with depression, pointing to a role as potential biomarkers. Further investigation of consensus proteomic features for depression is necessitated.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"24 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic rescue via mTOR inhibition in neuron-specific Pten knockout mice reveals AKT and mTORC1-site specific changes","authors":"Angelica D’Amore, Maria Sundberg, Rui Lin, Ella T. Lubbers, Kellen D. Winden, Lucy Yu, Kinga Gawlinska, Dawid Gawlinski, Sam G. Lopez, Yongho Choe, Emma V. Wightman, Yini Liang, Meera Modi, Christopher J. Yuskaitis, Henry Hing Cheong Lee, Alexander Rotenberg, Mustafa Sahin","doi":"10.1038/s41380-025-02916-2","DOIUrl":"https://doi.org/10.1038/s41380-025-02916-2","url":null,"abstract":"<p>Phosphatase and Tensin Homolog (PTEN) is a dual-specific protein and lipid phosphatase that regulates AKT and downstream signaling of the mechanistic target of rapamycin (mTOR). PTEN functions as a tumor suppressor gene whose mutations result in PTEN Hamartoma Tumor Syndrome (PHTS) characterized by increased cancer risk and neurodevelopmental comorbidity. Here, we generated a novel neuron-specific <i>Pten</i> knock-out mouse model (Syn-Cre/Pten HOM) to test the ability of pharmacologic mTOR inhibition to rescue <i>Pten</i> mutation-associated disease phenotypes in vivo and in vitro. We found that treatment with the mTOR inhibitor, everolimus, increased the survival of Syn-Cre/Pten HOM mice while some neurologic phenotypes persisted. Transcriptomic analyses revealed that in contrast to mice harboring a neuron-specific deletion of the Tuberous Sclerosis Complex 2 gene (Syn-Cre/Tsc2 KO), genes that are under AKT regulation were significantly increased in the Syn-Cre/Pten HOM mice. In addition, genes associated with synapse, extracellular matrix, and myelination were broadly increased in Syn-Cre/Pten HOM mouse neocortex. These findings were confirmed by immunostaining of cortical sections in vivo, which revealed excessive immunoreactivity of myelin basic protein and perineuronal nets (PNN), the specialized extracellular matrix surrounding fast-spiking parvalbumin (PV) interneurons. We also detected increased expression of Synapsin I/PSD95 positive synapses and network hyperactivity phenotypes in Syn-Cre/Pten HOM mice neurons compared to wild-type (WT) neurons in vitro. Strikingly, everolimus treatment rescued the number of synapses and network hyperactivity in the Syn-Cre/Pten HOM mice cortical neuron cultures. Taken together, our results revealed in vivo and in vitro molecular and neuronal network mechanisms underlying neurological phenotypes of PHTS. Notably, pharmacologic mTOR inhibition by everolimus led to successful downstream signaling rescue, including mTOR complex 1 (mTORC1) site-specific suppression of S6 phosphorylation, correlating with phenotypic rescue found in our novel neuron-specific Syn-Cre/Pten HOM mice.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"11 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preventing psychosis in people at clinical high risk: an updated meta-analysis by the World Psychiatric Association Preventive Psychiatry section","authors":"Amedeo Minichino, Cathy Davies, Olga Karpenko, Nikos Christodoulou, Rodrigo Ramalho, Sunil Nandha, Stefano Damiani, Umberto Provenzani, Cecilia Maria Esposito, Martina Maria Mensi, Renato Borgatti, Alberto Stefana, Philip McGuire, Paolo Fusar-Poli","doi":"10.1038/s41380-025-02902-8","DOIUrl":"https://doi.org/10.1038/s41380-025-02902-8","url":null,"abstract":"<p>Recently published large-scale randomised controlled trials (RCTs) have questioned the efficacy of preventive interventions in individuals at clinical high risk for psychosis (CHR-P). We conducted a systematic review and meta-analysis to include this new evidence and provide future directions for the field. We followed the PRISMA guidelines and a pre-registered protocol, with a literature search conducted from inception to November 2023. We included RCTs that collected data on psychosis transition (the primary outcome) in CHR-P. Secondary outcomes were symptoms severity and functioning. Investigated time points were 6,12,24,36, and +36 months. We used odd ratios (ORs) and standardised mean differences (SMD) as summary outcomes. Heterogeneity was estimated with the Higgins I². Twenty-four RCTs, involving 3236 CHR-P individuals, were included. Active interventions were Cognitive Behavioural Therapy (CBT), family-focused therapy, Integrated Psychological Therapy, antipsychotics, omega-3 fatty acids, CBT plus risperidone, minocycline, and other non-pharmacological approaches (cognitive remediation, sleep-targeted therapy, brain stimulation). Results showed no evidence that any of the investigated active interventions had a sustained and robust effect on any of the investigated outcomes in CHR-P, when compared to control interventions, including CBT on transition to psychosis at 12 months (9 RCTs; OR: 0.64; 95% CI: 0.39–1.06; I²: 21%; <i>P</i> = 0.08). These results highlight the need for novel treatment approaches in CHR-P. Future studies should consider the heterogeneity of this clinical population and prioritise stratification strategies and bespoke treatments.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"79 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gestational autoantibody exposure impacts early brain development in a rat model of MAR autism","authors":"Janna McLellan, Ana-Maria Iosif, Karol Cichewicz, Cesar Canales, Darlene Rahbarian, Melissa Corea, Melissa Bauman, Alex S. Nord, Judy Van de Water","doi":"10.1038/s41380-025-02907-3","DOIUrl":"https://doi.org/10.1038/s41380-025-02907-3","url":null,"abstract":"<p>Maternal autoantibody-related autism (MARA) is a subtype of autism characterized by the maternal production of specific patterns of autoantibodies during pregnancy, which significantly increases the likelihood of an autism diagnosis in their children. Multiple patterns of MARA autoantibodies (MARA-ABS) have been identified, and differences in the severity of the autism phenotype associated with each autoantibody pattern have been described. In this study, we utilized preclinical rat models to further elucidate the differential effects of MARA-AB exposure based on the known clinical patterns, including the originally reported pattern of lactate dehydrogenase A and B (LDHA/B) + collapsin response mediator protein 1 (CRMP1) + stress-induced phosphoprotein 1 (STIP1), as well as the more recently described patterns of CRMP1+CRMP2, CRMP1 + guanine deaminase (GDA), and STIP1+ neuron-specific enolase (NSE). We induced endogenous MARA-AB production in rat dams before pregnancy to expose offspring to the ABs throughout gestation. We found that in postnatal day 2 offspring exposed to MARA-ABS, the levels of brain and serum cytokines/chemokines/growth factors were altered based on the pattern of MARA-AB exposure. Further, bulk transcriptomic profiles of coronal sections containing hippocampal formation and the adjacent cortical and subcortical structures suggested changes in cellular proliferation and differentiation following MARA exposure. These combined observations demonstrate that gestational exposure to MARA-ABS alters early gene expression and immune signaling molecules, both of which may contribute to the altered neurodevelopment and behaviors associated with MARA.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"41 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of plasma inflammatory markers in late-life depression and conversion to dementia: a 3-year follow-up study","authors":"M. Bocharova, T. Borza, L. O. Watne, K. Engedal, J. T. O’Brien, G. Selbæk, A. V. Idland, J. Hodsoll, A. H. Young, D. Aarsland","doi":"10.1038/s41380-025-02908-2","DOIUrl":"https://doi.org/10.1038/s41380-025-02908-2","url":null,"abstract":"<p>Late-life depression (LLD) has been linked to increased likelihood of dementia, although mechanisms responsible for this association remain largely unknown. One feature frequently observed in both LLD and dementia is elevated levels of plasma inflammatory markers. The present study aimed to compare the levels of 12 plasma inflammatory markers between older people with LLD and controls, and to explore whether these markers, along with clinical characteristics, can predict dementia in patients with LLD within 3 years of follow-up. Using multiple linear regression with stepwise adjustment, we compared levels of plasma inflammatory markers (IL-1β, IL-1ra, IL-6, IL-10, IL-17a, IL-18, IL-33, TNFα, CD40L, IFN-γ, CCL-2 and CCL-4) between 136 inpatients with LLD (PRODE cohort) and 103 cognitively healthy non-depressed controls (COGNORM cohort). In the PRODE cohort, follow-up data was available for 139 patients (of them 123 had data on baseline plasma inflammatory markers); 36 (25.9%) developed dementia by Year 3 (n = 31 for those with cytokine data). Using Cox proportional hazards regression, we explored whether inflammatory markers and clinical characteristics of LLD (age of onset, treatment response, number of episodes) predicted progression to dementia during follow-up. Levels of IL-1ra, CCL-2, CCL-4, IFN-γ and IL-17a were significantly higher in LLD patients compared to controls in the majority of models. However, none of the inflammatory markers predicted progression from LLD to dementia in the PRODE cohort. Among clinical features, only poor response to treatment significantly predicted higher risk of progression to dementia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"62 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"βIV spectrin abundancy, cellular distribution and sensitivity to AKT/GSK3 regulation in schizophrenia","authors":"Jessica Di Re, Michela Marini, Syed Ibrar Hussain, Aditya K. Singh, Akshaya Venkatesh, Musaad A. Alshammari, Tahani K. Alshammari, Abdul-Rizaq Ali Hamoud, Ali Sajid Imami, Zahra Haghighijoo, Nickolas Fularcyzk, Laura Stertz, Derek Hawes, Angela Mosebarger, Jordan Jernigan, Claire Chaljub, Ralda Nehme, Consuelo Walss-Bass, Anton Schulmann, Marquis P. Vawter, Robert McCullumsmith, Robert D. Damoiseaux, Agenor Limon, Demetrio Labate, Michael F. Wells, Fernanda Laezza","doi":"10.1038/s41380-025-02917-1","DOIUrl":"https://doi.org/10.1038/s41380-025-02917-1","url":null,"abstract":"<p>Schizophrenia (SCZ) is a complex psychiatric disorder with unclear biological mechanisms. Spectrins, cytoskeletal proteins linked to neurodevelopmental disorders, are regulated by the AKT/GSK3 pathway, which is implicated in SCZ. However, the impact of SCZ-related dysregulation of this pathway on spectrin expression and distribution remains unexplored. Here, we show that βIV spectrin protein levels were reduced in neurons of the dorsolateral prefrontal cortex in SCZ postmortem samples compared to healthy control (HC) from the Human Brain Collection Core (HBCC). To investigate potential links between βIV spectrin and the AKT/GSK3 pathway, we analyzed the PsychEncode dataset, revealing elevated SPTBN4 and AKT2 mRNA levels with correlated gene transcription in both HCs and individuals with SCZ. Next, computational tools were employed to identify potential AKT and GSK3 phosphorylation sites on βIV spectrin, and two GSK3 sites were validated through in vitro assays. To assess whether βIV spectrin distribution and sensitivity to AKT/GSK3 are altered in SCZ, we used iPSC-derived neurons from two independent cohorts of patients with significantly increased familial genetic risk for the disorder. Alteration in βIV spectrin levels and sensitivity to AKT/GSK3 inhibitors were consistently observed across both cohorts. Importantly, a Random Forest classifier applied to βIV spectrin imaging achieved up to 98% accuracy in classifying cells by diagnosis in postmortem samples, and by diagnosis or diagnosis × perturbation in iPSC samples. These findings reveal altered βIV spectrin levels and AKT/GSK3 sensitivity in SCZ, identifying βIV spectrin image-based endophenotypes as robust, generalizable predictive biomarkers of SCZ, with the potential for scalable clinical applications.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"11 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}