The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Nakamura, Takumi; Takata, Atsushi

doi:10.1038/s41380-023-02005-2

Cited by 19 publications

(15 citation statements)

References 145 publications

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“…In addition to NFRKB, SETD1A (SET domain containing 1A) was foun to potentially regulate the second largest group of DETs identified for blood Thmem ce (Figure 2d). As member of the SET1/MLL family methyltransferases, SETD1A was d scribed as influencing chromatin conformation by modulating the methylation of histon H3 at lysine 4 (H3K4me3), resulting in transcriptional activation of the affected genes [51 Interestingly, it was reported that mutations in SETD1A substantially increase the risk f the development of schizophrenia [51,52].…”

Section: Resultsmentioning

confidence: 99%

Blood T Helper Memory Cells: A Tool for Studying Skin Inflammation in HS?

Witte

Schneider‐Burrus

Salinas

et al. 2023

IJMS

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Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful lesions on intertriginous body areas such as the axillary, inguinal, and perianal sites. Given the limited treatment options for HS, expanding our knowledge of its pathogenetic mechanisms is a prerequisite for novel therapeutic developments. T cells are assumed to play a crucial role in HS pathogenesis. However, it is currently unknown whether blood T cells show specific molecular alterations in HS. To address this, we studied the molecular profile of CD4+ memory T (Thmem) cells purified from the blood of patients with HS and matched healthy participants. About 2.0% and 1.9% of protein-coding transcripts were found to be up- and down-regulated in blood HS Thmem cells, respectively. These differentially expressed transcripts (DETs) are known to be involved in nucleoside triphosphate/nucleotide metabolic processes, mitochondrion organization, and oxidative phosphorylation. The detected down-regulation of transcripts involved in oxidative phosphorylation suggest a metabolic shift of HS Thmem cells towards glycolysis. The inclusion of transcriptome data from skin from HS patients and healthy participants in the analyses revealed that in HS skin lesions, the expression pattern of transcripts identified as DETs in blood HS Thmem cells was very similar to the expression pattern of the totality of protein-coding transcripts. Furthermore, there was no significant association between the extent of the expressional changes in the DETs of blood HS Thmem cells and the extent of the expressional changes in these transcripts in HS skin lesions compared to healthy donor skin. Additionally, a gene ontology enrichment analysis did not demonstrate any association of the DETs of blood HS Thmem cells with skin disorders. Instead, there were associations with different neurological diseases, non-alcoholic fatty liver disease, and thermogenesis. The levels of most DETs linked to neurological diseases showed a positive correlation to each other, suggesting common regulatory mechanisms. In summary, the transcriptomic changes in blood Thmem cells observed in patients with manifest cutaneous HS lesions do not appear to be characteristic of the molecular changes in the skin. Instead, they could be useful for studying comorbidities and identifying corresponding blood biomarkers in these patients.

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Section: Resultsmentioning

confidence: 99%

Blood T Helper Memory Cells: A Tool for Studying Skin Inflammation in HS?

Witte

Schneider‐Burrus

Salinas

et al. 2023

IJMS

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“…The ability to generate iPSCs from well-characterized schizophrenia patients and healthy subjects enables us to generate neuronal cells that have the same genetic background as the subjects and interrogate biological differences that result from the collective effect of the complex genetic backgrounds [58][59][60][61][62]. There is convergent data, including from iPSCbased studies, that implicate deficits in synaptic biology in the etiopathogenesis of schizophrenia [63][64][65]. Schizophrenia is typically diagnosed in adolescence or early adulthood [66].…”

Section: Discussionmentioning

confidence: 99%

Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia

et al. 2023

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Background Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia. Methods We generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia. Results Cortical neurons expressing layer III marker CUX1, but not those expressing layer V marker CTIP2, showed significant reduction in dendritic spine density in schizophrenia, mirroring findings in postmortem studies. Transcriptomic experiments in iPSC-derived cortical neurons showed that differentially expressed genes in schizophrenia were enriched for genes implicated in schizophrenia in genome-wide association and exome sequencing studies. Moreover, most of the differentially expressed genes implicated in schizophrenia genetic studies had lower expression levels in schizophrenia cortical neurons. Network analysis of differentially expressed genes led to identification of NRXN3 as a hub gene, and follow-up experiments showed specific reduction of the NRXN3 204 isoform in schizophrenia neurons. Furthermore, overexpression of the NRXN3 204 isoform in schizophrenia neurons rescued the spine and synapse deficits in the cortical neurons while knockdown of NRXN3 204 in healthy neurons phenocopied spine and synapse deficits seen in schizophrenia cortical neurons. The antipsychotic clozapine increased expression of the NRXN3 204 isoform in schizophrenia cortical neurons and rescued the spine and synapse density deficits. Conclusions Taken together, our findings in iPSC-derived cortical neurons recapitulate cell type-specific findings in postmortem studies in schizophrenia and have led to the identification of a specific isoform of NRXN3 that modulates synaptic deficits in schizophrenia neurons.

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“…In identifying potential therapeutics, we noticed that the KMT2C target genes detected by ChIP-seq of the adult brain (Fig. 2i-k and Supplementary Table 4a) strikingly overlap with the targets of SETD1A [13] (Supplementary Table 6), another histone methyltransferase catalytic unit known as an established risk gene for schizophrenia and other neurodevelopmental disorders [12,14,15], in the brain (Fig. 5a, P = 2.83 × 10 −86 , hypergeometric test).…”

Section: Colocalization Of Kmt2c With H3k4me3 and Downregulated Degs ...mentioning

confidence: 99%

“…De novo LOF variants of KMT2C were also identified in patients clinically diagnosed with Kleefstra syndrome, whose characteristic symptoms include autistic-like features [11]. Besides, other members of the H3K4 methylation regulators were reported to be associated with other neurodevelopmental syndromes with ASD symptoms and neuropsychiatric disorders such as schizophrenia [12][13][14][15]. Therefore, KMT2C haploinsufficiency is an established causative risk factor of ASD and NDD with autistic symptoms, and it has been indicated that H3K4 methylation plays an important role in brain development and cognitive functions [16]; however, little is known about how it causes neurodevelopmental deficits and how these conditions can be treated.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor

Nakamura,

Yoshihara,

Tanegashima

et al. 2024

Mol Psychiatry

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Recent studies have consistently demonstrated that the regulation of chromatin and gene transcription plays a pivotal role in the pathogenesis of neurodevelopmental disorders. Among many genes involved in these pathways, KMT2C, encoding one of the six known histone H3 lysine 4 (H3K4) methyltransferases in humans and rodents, was identified as a gene whose heterozygous loss-of-function variants are causally associated with autism spectrum disorder (ASD) and the Kleefstra syndrome phenotypic spectrum. However, little is known about how KMT2C haploinsufficiency causes neurodevelopmental deficits and how these conditions can be treated. To address this, we developed and analyzed genetically engineered mice with a heterozygous frameshift mutation of Kmt2c (Kmt2c+/fs mice) as a disease model with high etiological validity. In a series of behavioral analyses, the mutant mice exhibit autistic-like behaviors such as impairments in sociality, flexibility, and working memory, demonstrating their face validity as an ASD model. To investigate the molecular basis of the observed abnormalities, we performed a transcriptomic analysis of their bulk adult brains and found that ASD risk genes were specifically enriched in the upregulated differentially expressed genes (DEGs), whereas KMT2C peaks detected by ChIP-seq were significantly co-localized with the downregulated genes, suggesting an important role of putative indirect effects of Kmt2c haploinsufficiency. We further performed single-cell RNA sequencing of newborn mouse brains to obtain cell type-resolved insights at an earlier stage. By integrating findings from ASD exome sequencing, genome-wide association, and postmortem brain studies to characterize DEGs in each cell cluster, we found strong ASD-associated transcriptomic changes in radial glia and immature neurons with no obvious bias toward upregulated or downregulated DEGs. On the other hand, there was no significant gross change in the cellular composition. Lastly, we explored potential therapeutic agents and demonstrate that vafidemstat, a lysine-specific histone demethylase 1 (LSD1) inhibitor that was effective in other models of neuropsychiatric/neurodevelopmental disorders, ameliorates impairments in sociality but not working memory in adult Kmt2c+/fs mice. Intriguingly, the administration of vafidemstat was shown to alter the vast majority of DEGs in the direction to normalize the transcriptomic abnormalities in the mutant mice (94.3 and 82.5% of the significant upregulated and downregulated DEGs, respectively, P < 2.2 × 10−16, binomial test), which could be the molecular mechanism underlying the behavioral rescuing. In summary, our study expands the repertoire of ASD models with high etiological and face validity, elucidates the cell-type resolved molecular alterations due to Kmt2c haploinsufficiency, and demonstrates the efficacy of an LSD1 inhibitor that might be generalizable to multiple categories of psychiatric disorders along with a better understanding of its presumed mechanisms of action.

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The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Cited by 19 publications

References 145 publications

Blood T Helper Memory Cells: A Tool for Studying Skin Inflammation in HS?

Blood T Helper Memory Cells: A Tool for Studying Skin Inflammation in HS?

Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia

Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor

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