Neuropsin in mental health

Bukowski, Lina; Chernomorchenko, Ana; Starnawska, Anna; Mors, Ole; Staunstrup, Nicklas Heine; Børglum, Anders; Qvist, Per

doi:10.1186/s12576-020-00753-2

Cited by 9 publications

(7 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have implicated KLK8 in the pathogenesis of several psychiatric disorders, including anxiety and depression [ 17 , 18 ]. In the present study, we first examined whether the depressive phenotypes of CUMS-exposed mice are associated with hippocampus KLK8 expression.…”

Section: Resultsmentioning

confidence: 99%

“…KLK8 (also known as neuropsin) is highly expressed in the hippocampus, amygdala, and other brain regions associated with emotion management, and plays a key role in neuroplasticity, learning, and memory processes [ 17 , 18 , 31 , 32 ]. Previous studies have suggested the relationship between KLK8 and behavioral regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Tissue kallikrein-related peptidase 8 (KLK8), also named neuropsin, is a trypsin-like serine protease expressed abundantly in the central nervous system (CNS) [ 17 ]. KLK8 has been implicated in the pathogenesis of several psychiatric disorders, such as anxiety, depression, and schizophrenia [ 17 , 18 ]. Recently, Starnawska et al identified an association between blood DNA methylation levels in promoter regions of KLK8 and severity of depression symptoms in a large Danish cohort of monozygotic twins [ 19 ] and four independent methylomic cohorts [ 20 ], further supporting the implication of KLK8 in depression symptomatology.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1

Xu¹,

Du²,

Liu³

et al. 2023

Cell Death Dis

View full text Add to dashboard Cite

Neuronal apoptosis has been well-recognized as a critical mediator in the pathogenesis of depressive disorders. Tissue kallikrein-related peptidase 8 (KLK8), a trypsin-like serine protease, has been implicated in the pathogenesis of several psychiatric disorders. The present study aimed to explore the potential function of KLK8 in hippocampal neuronal cell apoptosis associated with depressive disorders in rodent models of chronic unpredictable mild stress (CUMS)-induced depression. It was found that depression-like behavior in CUMS-induced mice was associated with hippocampal KLK8 upregulation. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency attenuated CUMS-induced depression-like behaviors and hippocampal neuronal apoptosis. In HT22 murine hippocampal neuronal cells and primary hippocampal neurons, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce neuron apoptosis. Mechanistically, it was identified that the neural cell adhesion molecule 1 (NCAM1) may associate with KLK8 in hippocampal neurons as KLK8 proteolytically cleaved the NCAM1 extracellular domain. Immunofluorescent staining exhibited decreased NCAM1 in hippocampal sections obtained from mice or rats exposed to CUMS. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency largely prevented CUMS-induced loss of NCAM1 in the hippocampus. Both adenovirus-mediated overexpression of NCAM1 and NCAM1 mimetic peptide rescued KLK8-overexpressed neuron cells from apoptosis. Collectively, this study identified a new pro-apoptotic mechanism in the hippocampus during the pathogenesis of CUMS-induced depression via the upregulation of KLK8, and raised the possibility of KLK8 as a potential therapeutic target for depression.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1

Xu¹,

Du²,

Liu³

et al. 2023

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…Neuropsin ( Klk8 ) is another gene affected in Setd1b cKO mice that plays a complex role in memory function. It regulates the extracellular matrix, leads to spatial reference memory impairment when deleted in mice (Tamura et al , 2006 ) and has been implicated with mental diseases (Bukowski et al , 2020 ) (Fig 3E ).…”

Section: Resultsmentioning

confidence: 99%

Postnatal expression of the lysine methyltransferase SETD1B is essential for learning and the regulation of neuron‐enriched genes

et al. 2021

View full text Add to dashboard Cite

In mammals, histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Among these enzymes, SETD1B (SET domain containing 1b) has been linked to syndromic intellectual disability in human subjects, but its role in the mammalian postnatal brain has not been studied yet. Here, we employ mice deficient for Setd1b in excitatory neurons of the postnatal forebrain, and combine neuron-specific ChIP-seq and RNAseq approaches to elucidate its role in neuronal gene expression. We observe that Setd1b controls the expression of a set of genes with a broad H3K4me3 peak at their promoters, enriched for neuron-specific genes linked to learning and memory function. Comparative analyses in mice with conditional deletion of Kmt2a and Kmt2b histone methyltransferases show that SETD1B plays a more pronounced and potent role in regulating such genes. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-dependent regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

show abstract

“…Notably, inactivation of KLK8 has protective effects against depressive-like behaviors and memory impairment initially induced by chronic stress in mice [ 23 , 26 ]. A more comprehensive review of the role of KLK8 in mental health phenotypes is available elsewhere [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation of the KLK8 gene in depression symptomatology

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background Depression is a common, complex, and debilitating mental disorder estimated to be under-diagnosed and insufficiently treated in society. Liability to depression is influenced by both genetic and environmental risk factors, which are both capable of impacting DNA methylation (DNAm). Accordingly, numerous studies have researched for DNAm signatures of this disorder. Recently, an epigenome-wide association study of monozygotic twins identified an association between DNAm status in the KLK8 (neuropsin) promoter region and severity of depression symptomatology. Methods In this study, we aimed to investigate: (i) if blood DNAm levels, quantified by pyrosequencing, at two CpG sites in the KLK8 promoter are associated with depression symptomatology and depression diagnosis in an independent clinical cohort and (ii) if KLK8 DNAm levels are associated with depression, postpartum depression, and depression symptomatology in four independent methylomic cohorts, with blood and brain DNAm quantified by either MBD-seq or 450 k methylation array. Results DNAm levels in KLK8 were not significantly different between depression cases and controls, and were not significantly associated with any of the depression symptomatology scores after correction for multiple testing (minimum p value for KLK8 CpG1 = 0.12 for ‘Depressed mood,’ and for CpG2 = 0.03 for ‘Loss of self-confidence with other people’). However, investigation of the link between KLK8 promoter DNAm levels and depression-related phenotypes collected from four methylomic cohorts identified significant association (p value < 0.05) between severity of depression symptomatology and blood DNAm levels at seven CpG sites. Conclusions Our findings suggest that variance in blood DNAm levels in KLK8 promoter region is associated with severity of depression symptoms, but not depression diagnosis.

show abstract

Neuropsin in mental health

Cited by 9 publications

References 62 publications

Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1

Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1

Postnatal expression of the lysine methyltransferase SETD1B is essential for learning and the regulation of neuron‐enriched genes

DNA methylation of the KLK8 gene in depression symptomatology

Contact Info

Product

Resources

About