Double-strand breaks induced by learning-like activity may increase risk of de novo mutations in schizophrenia

Lu, Li-Fang; Wang, Jie; Liu, Kun-Ze; Yi, Xi-Nan; Ma, Zaitian; Li, Yunqing; Feng, Ren-Jun

doi:10.1016/j.ajp.2022.103292

Cited by 2 publications

(1 citation statement)

References 15 publications

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“…Stott et al demonstrated that repeated cycles of DSBs and their repair might increase de novo gene mutations in neurons and glia, potentially increasing the risk of neurological and psychiatric disorders ( 58 ). Furthermore, DSBs and single-strand breaks are thought to affect DNA methylation and demethylation and may play pivotal roles in the development of SZ ( 55 , 59 ). Thus, based on findings regarding the role of DNA damage and repair in pathogenesis, it is considered that physiological DNA breaks, increased neural activity mediated by glutamate receptors ( 60 ), and oxidative stress are the causes of DNA damage in the brain.…”

Section: Discussionmentioning

confidence: 99%

Evidence for increased DNA damage repair in the postmortem brain of the high stress-response group of schizophrenia

Shishido,

Kunii,

Hino

et al. 2023

Front. Psychiatry

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BackgroundSchizophrenia (SZ) is a disorder diagnosed by specific symptoms and duration and is highly heterogeneous, clinically and pathologically. Although there are an increasing number of studies on the association between genetic and environmental factors in the development of SZ, the actual distribution of the population with different levels of influence of these factors has not yet been fully elucidated. In this study, we focused on stress as an environmental factor and stratified SZ based on the expression levels of stress-responsive molecules in the postmortem prefrontal cortex.MethodsWe selected the following stress-responsive molecules: interleukin (IL) -1β, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, glucocorticoid receptor, brain-derived neurotrophic factor, synaptophysin, S100 calcium-binding protein B, superoxide dismutase, postsynaptic density protein 95, synuclein, apolipoprotein A1 (ApoA1), ApoA2, and solute carrier family 6 member 4. We performed RNA sequencing in the prefrontal gray matter of 25 SZ cases and 21 healthy controls and conducted a hierarchical cluster analysis of SZ based on the gene expression levels of stress-responsive molecules, which yielded two clusters. After assessing the validity of the clusters, they were designated as the high stress-response SZ group and the low stress-response SZ group, respectively. Ingenuity Pathway Analysis of differentially expressed genes (DEGs) between clusters was performed, and Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was conducted on four cases each in the high and low stress-response SZ groups to validate DNA damage.ResultsWe found higher prevalence of family history of SZ in the low stress-response SZ group (0/3 vs. 5/4, p = 0.04). Pathway analysis of DEGs between clusters showed the highest enrichment for DNA double-strand break repair. TUNEL staining showed a trend toward a lower percentage of TUNEL-positive cells in the high stress-response SZ group.ConclusionOur results suggest that there are subgroups of SZ with different degrees of stress impact. Furthermore, the pathophysiology of these subgroups may be associated with DNA damage repair. These results provide new insights into the interactions and heterogeneity between genetic and environmental factors.

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Section: Discussionmentioning

confidence: 99%

Evidence for increased DNA damage repair in the postmortem brain of the high stress-response group of schizophrenia

Shishido,

Kunii,

Hino

et al. 2023

Front. Psychiatry

View full text Add to dashboard Cite

show abstract

Double-strand breaks induced by learning-like activity may increase risk of de novo mutations in schizophrenia

Cited by 2 publications

References 15 publications

Evidence for increased DNA damage repair in the postmortem brain of the high stress-response group of schizophrenia

Evidence for increased DNA damage repair in the postmortem brain of the high stress-response group of schizophrenia

Causes and countermeasures for the increased infection and COVID-19 mortality rates in patients with schizophrenia

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