Uticaj polimorfizama FKBP5 gena, traume u detinjstvu i neuroticizma na rizik od psihotičnog poremećaja

Abstract

Spektar psihotičnih poremećaja, od kojih je najteže oboljenje shizofrenija, čine složene nasledne poligenske bolesti kod kojih, pored genetičkih faktora, bitnu ulogu u etiologiji bolesti imaju psihosocijalni faktori rizika, kao što su trauma u detinjstvu i neuroticizam. Neurobiološki mehanizam kojim bi se objasnio uticaj psihosocijalnih faktora rizika na obolevanje od psihotičnog poremećaja još uvek nije poznat. Jedan od ponuđenih modela bolesti kojim bi se pokazala njihova veza jeste dijateza-stres model. Ovaj model ističe značaj interakcije biološke vulnerabilnost na stres (povišena stres-senzitivnost) i nepovoljnih životnih događaja u ranom životnom dobu (trauma u detinjstvu) na podložnost za nastanak psihotičnog poremećaja. Takođe, psihološki faktor rizika (neuroticizam) uključen je u ovaj model s obzirom da je neuroticizam marker stresvulnerabilnosti, odnosno fenotip kojim se opisuje povišena senzitivnost na stres. Interesantno je da je povišena senzitivnost na stres uočena ne samo kod pacijenata sa psihotičnim poremećajem, već i kod njihovih prvostepenih srodnika, što govori u prilog nasledne osnove stres-senzitivnosti. Najprihvaćeniji neurobiološki mehanizam dijateza-stres modela jeste poremećaj aktivnosti hipotalamo-hipofizno-adrenalne (HPA) osovine. Molekularna osnova disregulacije HPA osovine proučava se najviše u domenu poremećene glukokortikoidne signalizacije, gde glavnu ulogu ima glukokortikoidni receptor (GR). Ključni regulator GR jeste protein FK506-binding protein 51(FKBP51), ko-šaperon (co-chaperone) heatschock proteina 90 (hsp90), koji posreduje u translokaciji kortizol-GR kompleksa iz citoplazme u nukleus, a time i u GR-posredovanoj genskoj transkripciji. Gen koji kodira ovaj protein jeste FKBP5 gen. Ispitivanja polimorfizama u FKBP5 genu pokazala su da određeni rizični aleli imaju funkcionalni uticaj na ekspresiju FKBP51, kao i da u interakciji sa stresnim događajima predstavljaju značajne prediktore za različitu psihopatologiju indukovanu stresom, među kojima su i psihotični pormećaji...

Psychotic disorders and schizophrenia, as the most severe psychotic disorder, are complex, heritable and polygenic diseases in which, beside genetics influence, psyschosocial risk factors, such as childhood trauma and neuroticism, play important roles. Neurobiological mechanisms which could explain relationship between psychosocial risk factors and psychotic disorders are still unknown. One of the proposed model is diathesisstres model of psychosis. This model suggests that interaction between biological vulnerability to stress (increased stress-sensitivity) and stressful life events is crucial for the development of psychotic disorders. Additionally, this model highlights the role of psychological risk factor (neuroticism) as the most promising marker for stressvulnerability, and thus phenotype for increased stress-sensitivity. Notably, increased stress-sensitivity is observed not only in patients with psychotic dirorders but also in their healthy siblings, suggesting that stress-sensitivity could be heritable marker. The most accepted neurobiological mechanism of diathesis-stress model is altered activity of the hypothalamic-pituitary-adrenal (HPA) axis. Molecular pathway for dysregulation of the HPA axis is studied mostly in the domain of impaired glucocorticoid signalization, where the glucocorticoid receptor (GR) has the main role. A key regulator of the GR activity is FK506-binding protein 51 (FKBP51), co-chaperone (co-chaperone) of heat-schock protein 90 (hsp90), which mediates the translocation of cortisol-GR complex from the cytoplasm to the nucleus, and thus in the GR-mediated gene transcription. The gene encoding this protein is FKBP5 gene. Studies of the FKBP5 polymorphisms have shown that certain risk alleles have functional significance on the expression of FKBP51, and interact with stressful life events to predict stress-induced psychopathology such as psychotic disorders. Given that the role of FKBP5 gene in diathesis-stress model of psychotic disorders is a new topic in psychotic research field, further investigation of the impact of the FKBP5 genetic variants and childhood trauma on the disease, as well as its potential effect on the phenotype of stress-sensitivity (neuroticism) are warranted...