Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation.
OBJECTIVE
Neuroimaging findings have identified lower cortical gray matter volume in schizophrenia. Apoptosis (programmed cell death) has been proposed as a contributing pathophysiological mechanism. Levels of antiapoptotic Bcl-2 protein are low in the temporal cortex of schizophrenia patients. Bcl-2 interacts with the proapoptotic Bax protein at an upstream checkpoint to regulate the activation of apoptosis by caspase-3 and other proteolytic caspase proteins. A high Bax/Bcl-2 ratio is associated with greater vulnerability to apoptotic activation, while a high caspase-3 level is often associated with apoptotic activity. It was hypothesized that the Bax/Bcl-2 ratio, but not caspase-3, would be high in the temporal cortex of patients with chronic schizophrenia.


METHODS
Bax, Bcl-2, and caspase-3 proteins were measured by semiquantitative Western blot in Brodmann's area 21 (middle temporal gyrus) of postmortem tissue from patients with schizophrenia (N=15), bipolar disorder (N=15), or major depression (N=15) and nonpsychiatric comparison subjects (N=15).


RESULTS
The Bax/Bcl-2 ratio was 50% higher in the schizophrenia patients than the nonpsychiatric comparison subjects. The level of caspase-3 (inactive zymogen and activated subunits) was not significantly different.


CONCLUSIONS
The higher Bax/Bcl-2 ratio suggests that cortical cells are vulnerable to apoptosis in chronic schizophrenia. However, the normal caspase-3 level suggests that apoptosis is not active in this illness phase. Furthermore, the results appear to distinguish the pathophysiology of schizophrenia from most classic neurodegenerative disorders, in which postmortem caspase-3 levels are high. Further studies are needed to investigate the implications of abnormal apoptotic proteins in schizophrenia.
Jarskog
L Fredrik
LF
Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill 27599-7160, USA. jarskog@med.unc.edu
Selinger
Elzbieta S
ES
Lieberman
Jeffrey A
JA
Gilmore
John H
JH
D000368:Aged; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D013702:Temporal Lobe / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
D014150:Antipsychotic Agents; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D006220:Haloperidol