INVESTIGATION OF FASCICULATION AND ELONGATION PROTEIN ζ-1 (FEZ1) IN PERIPHERAL BLOOD REVEALS DIFFERENCES IN GENE EXPRESSION IN PATIENTS WITH SCHIZOPHRENIA
Vachev TI1, Stoyanova VK, Ivanov HY, Minkov IN, Popov NT
*Corresponding Author: Associate Professor Vili K. Stoyanova, M.D., Ph.D., Department of Pediatrics and Medical Genetics, Medical University ‒ Plovdiv, 15A Vasil Aprilov St., 4000 Plovdiv, Bulgaria. Tel: +359-32- 602-431; Fax: +359-32-602-593. E-mail: vi1sto@abv.bg
page: 31

DISCUSSION

Despite the identification of numerous SZ susceptibility genes, the pathology of SZ still remains unknown. At the molecular level, a large number of potential DISC1 binding partners have been identified from a yeast two-hybrid screen [12], many of which are also involved in neurodevelopmental processes implicated in the patho-physiology of psychiatric disorders. Experiments with primates and rodents demonstrate that FEZ1 and DISC1 have overlapping temporal and spatial expression patterns [17,18]. Both proteins are expressed in the pyramidal neurons of the developing hippocampus, the cerebral neocortex and the olfactory bulb. Moreover, disruption of the DISC1/FEZ1 interaction inhibits DISC1-stimulated neurite outgrowth in PC12 cells [8], thus, decreased FEZ1 levels could influence DISC1-stimulated functions. On the one hand, this study is the first describing a FEZ1 gene expression change in peripheral blood of patients with SZ; on the other hand, this change corresponds to the down-regulation in prefrontal cortex and hippocampus of schizophrenic patients [9]. Due to the fact that FEZ1 interacts with DISC1, a susceptibility gene for major mental disorders to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus. We assume that any interaction related to another FEZ1 partner would be compromised or at least influenced due to changes in the expression of the FEZ1 transcript that would change the level of translated protein and its involvement in complexes associated with susceptibility for SZ functions (Figure 1). Thus, our results provide support for a model of SZ pathogenesis that includes the regulatory effects on FEZ1 gene expression in peripheral blood specific for patients with exacerbation of SZ. One obvious limitation of previous expression studies is the use of human postmortem brain tissue for quantitative analyses of gene expression profile, primarily because postmortem brain tissue from SZ patients is extremely rare and highly prized. Additionally, identification of gene expression profile can be complicated by a variety of confounding factors such as pH, drugs, cause of death, etc. In contrast, in attempts to overcome these limitations, we used RNA storage and extraction systems that block and preserve RNA for downstream expression study, so that the expression level that we identified really reflects the current physiological state of the analyzed patients. All these changes in expression levels probably are not due to gene polymorphisms, as such was not detected in a large SZ cohort [19], but can be attributed to various epigenetic mechanisms that alter distinct molecular pathways. As hypomethylation was observed in the exonic region of HTR2A and MB-COMT promoters in the DNA derived from saliva in SZ [20], it is possible that epigenetic factors leading to down-regulation of FEZ1 in schizophrenic brains may also reflect in peripheral blood and result in the reduction of the expression in these tissues. However, additional studies applying RNA sequencing analysis for identifying peripheral blood-based biomarkers that could represent brain expression and epigenetic aberrations remain a key step in implication of these findings in pathogenesis, diagnosis and future therapy.



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