Uticaj polimorfizama FKBP5 gena, traume u detinjstvu i neuroticizma na rizik od psihotičnog poremećaja
The effect of the FKBP5 polymorphisms, childhood trauma and neuroticism on psychotic disorders.
Author
Mihaljević, Marina M.Mentor
Marić-Bojović, NađaCommittee members
Novaković, Ivana
Lečić-Toševski, Dušica
Marković, Ivanka

Đukić-Dejanović, Slavica
Metadata
Show full item recordAbstract
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 sam...o 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-sens...itivity 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...