Glycogen synthase kinase-3β immunoreactivity is reduced in the prefrontal cortex in schizophrenia

Beasley, Clare L.; Cotter, David; Khan, Naheed L.; Pollard, Claire; Sheppard, Paul A. S.; Varndell, Ian M.; Lovestone, Simon; Anderton, Brian H.; Everall, Ian

doi:10.1016/s0304-3940(01)01688-3

Cited by 116 publications

(67 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…17,20 Several researches have reported that abnormalities of neural cell adhesion, neuronal function, and Wnt/Wingless exist in schizophrenia. [10][11][12][13][14][15]18,19,[23][24][25][26] Third, APC is located at 5q21-22, which has been previously reported to be linked with schizophrenia. 27,28 Three SNPs of APC are associated with schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia

Cui

Jiang

et al. 2005

Mol Psychiatry

View full text Add to dashboard Cite

The etiology of schizophrenia is unclear, although family, twin, and linkage studies implicate genetic factors. Here, we identified adenomatous polyposis coli (APC), a tumor suppressor gene, as a risk factor for schizophrenia. We compared leukocytic gene expression patterns of six pairs of patients with schizophrenia and healthy controls by microarray. APC expression levels were significantly increased in all patients compared to healthy controls. To confirm the findings of microarray analysis, we measured expression levels of APC in the leukocytes from 30 relapse patients taking antipsychotic medication, 29 first-episode drug-naïve patients, and 30 healthy controls using real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR). APC expression levels were significantly increased in leukocytes of schizophrenics both taking and not taking antipsychotic medication and hence the increase of APC expression was not due to antipsychotic medication. APC is located at 5q21-22, which has been previously reported to be linked with schizophrenia. Further, we performed the transmission disequilibrium test (TDT) and TDT based on haplotypes to search for the association between schizophrenia and APC by examining 163 parent-offspring trios of Chinese descent. We analyzed three single-nucleotide polymorphisms (SNPs) (rs2229992, rs42427, rs465899) at the exon region of APC. TDT showed that the three SNPs are significantly associated with schizophrenia (TDT v 2 ¼ 4.23, Po0.05; 4.15, Po0.05; 8.49 Po0.01, respectively; HHRRv 2 ¼ 5.54, Po0.05; 4.40, Po0.05; 9.79, Po0.01, respectively). We found a significant association between the APC haplotypes from rs2229992-rs42427-rs465899 and schizophrenia (Global v 2 ¼ 44.376,df ¼ 7, Po0.001). The C-A-T haplotype has a frequency of more than 57% and has a strong association with schizophrenia (v 2 ¼ 15.04, Po0.001). These results indicate that the APC may be a candidate gene conferring susceptibility to schizophrenia and also may be associated with reduced vulnerability to cancer in schizophrenia.

show abstract

Section: Discussionmentioning

confidence: 99%

“…9 Recently, evidences for potential disturbances of Wnt signaling pathways in schizophrenia have accumulated. [10][11][12][13][14][15] However, as far as the authors are aware, the involvement of APC in schizophrenia has not been reported. The immunoprecipitation experiment results suggested that APC is involved in cell adhesion.…”

mentioning

confidence: 94%

The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia

Cui

Jiang

et al. 2005

Mol Psychiatry

View full text Add to dashboard Cite

show abstract

“…100 When the phosphorylation levels of GSK-3b at Ser9 (that is, the site phosphorylated by Akt1) were measured in frontal cortex and lymphocytes from individuals with schizophrenia, decreased levels were found, although levels of the GSK-3b form phosphorylated at Tyr216 were not abnormal in either the lymphocytes or frontal cortex. 75 Other neuropathologic studies of individuals with schizophrenia reported that GSK3b levels were decreased in the prefrontal cortex from these individuals 101 and that phospho-Ser9-GSK-3b levels were decreased in the frontal cortex of these individuals. 84 Decreased levels of GSK-3b were also observed in the cerebrospinal fluid of individuals with schizophrenia, with no correlation with antipsychotic dose.…”

Section: Possible Mechanisms Of Antipsychotic-induced Disordered Glucmentioning

confidence: 97%

Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway

2008

View full text Add to dashboard Cite

The exact therapeutic mechanism of action of antipsychotic drugs remains unclear. Recent evidence has shown that second-generation antipsychotic drugs (SGAs) are differentially associated with metabolic side effects compared to first-generation antipsychotic drugs (FGAs). Their proclivity to cause metabolic disturbances correlates, to some degree, with their comparative efficacy. This is particularly the case for clozapine and olanzapine. In addition, the insulin signaling pathway is vital for normal brain development and function. Abnormalities of this pathway have been found in persons with schizophrenia and antipsychotic drugs may ameliorate some of these alterations. This prompted us to hypothesize that the therapeutic antipsychotic and adverse metabolic effects of antipsychotic drugs might be related to a common pharmacologic mechanism. This article reviews insulin metabolism in the brain and related abnormalities associated with schizophrenia with the goals of gaining insight into antipsychotic drug effects and possibly also into the pathophysiology of schizophrenia. Finally, we speculate about one potential mechanism of action (that is, functional selectivity) that would be consistent with the data reviewed herein and make suggestions for the future investigation that is required before a therapeutic agent based on these data can be realized.

show abstract

“…In this context, GSK-3b is regarded as playing a major role in the pathogenesis of various neurological disorders including schizophrenia (see also below). Indeed, several reports have shown that GSK-3b levels or its phosphorylation state (Ser-9-GSK3b), are altered among schizophrenic individuals (Kozlovsky et al, 2000(Kozlovsky et al, , 2001Beasley et al, 2001;Emamian et al, 2004). Moreover, GSK-3b has been shown to be a target of the action mood-stabilizers such as lithium and VPA ( Klein and Melton, 1996;Chen et al, 1999;Hall et al, 2002), antipsychotics drugs, as clozapine, haloperidol and risperidone (Alimohamad et al, 2005a, b) and psychotomimetics drugs, which induce an schizophreniclike state in humans and animal models (Svenningsson et al, 2003;Ahn et al, 2005).…”

Section: Schizophrenia and Polymorphisms In Frizzled 3 And Gsk3bmentioning

confidence: 99%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

View full text Add to dashboard Cite

In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/b-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/b-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

show abstract

Glycogen synthase kinase-3β immunoreactivity is reduced in the prefrontal cortex in schizophrenia

Cited by 116 publications

References 17 publications

The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia

The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia

Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway

The ups and downs of Wnt signaling in prevalent neurological disorders

Contact Info

Product

Resources

About