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|Title: ||Upregulation of CaMKIIβ and Nogo-C mRNA in Schizophrenia and the Prevalence of CAA Insert in the 3’UTR of the Nogo Gene|
|Authors: ||Novak, Gabriela|
|Advisor: ||Seeman, Philip|
|Issue Date: ||1-Aug-2008|
|Abstract: ||Schizophrenia may result from altered gene expression leading to abnormal neurodevelopment. In a search for genes with altered expression in schizophrenia, cDNA library subtractive hybridization experiments using post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were performed.
I found the mRNA of two neurodevelopmentally important genes, Nogo (RTN4) and calcium/calmodulin-dependent protein kinase II beta (CaMKIIβ), to be overexpressed in post-mortem frontal cortex tissues from patients who suffered with schizophrenia. I used the quantitative real-time polymerase chain reaction method to determined the mRNA levels of these genes in tissues from age- and sex-matched individuals.
Nogo is a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The gene produces three splice variants, Nogo-A, B and C. I found Nogo-C mRNA to be overexpressed by 26% in schizophrenia. I also found a 17% reduction of Nogo-B mRNA in samples from individuals who had been diagnosed with severe depression. Furthermore, I showed that there is a direct correlation between the expression of both Nogo-A and -C and the presence of a CAA insert in the 3’UTR of the Nogo gene.
CaMKII is a kinase localized at the postsynaptic density. The holoenzyme is primarily composed of the subunits α and β, encoded by two separate genes. It influences the expression of many neuroreceptors, in particular receptors of the glutamatergic pathway. CaMKII also mediates neural maturation during puberty, a time of onset of schizophrenia. The expression of CaMKIIα was elevated 29% in frontal cortex tissues of patients who suffered from depression. The expression of CaMKIIβ was elevated 27% in tissues of schizophrenia patients and 36% in tissues of patients diagnosed with depression. Upregulation of CaMKIIβ was associated with the presence of the CAA insert in at least one copy of the Nogo gene in a group containing both healthy subjects and patients with mental illness, possibly linking the CaMKII and Nogo pathways. The values for the expression of Nogo, CaMKIIα and CaMKIIβ were normalized to β-glucuronidase expression to minimize the effects of mRNA degradation. These results confirm that upregulation of Nogo-C and CaMKIIβ is likely associated with schizophrenia.|
|Appears in Collections:||Doctoral|
Department of Pharmacology and Toxicology - Doctoral theses
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