Pro-apoptotic Par-4 and dopamine D2 receptor in temporal cortex in schizophrenia, bipolar disorder and major depression.
Although the etiology of schizophrenia remains unknown, diverse neuropathological evidence suggests a disorder of synaptic connectivity. Apoptosis is a form of cell death that helps determine synaptic circuitry during neurodevelopment and altered regulation of apoptosis has been implicated in schizophrenia. Prostate apoptosis response-4 (Par-4) is an upstream regulator of apoptosis preferentially localized to synapses. Brain Par-4 levels are upregulated in response to pro-apoptotic stimuli in rodent models and in patients with classic neurodegenerative diseases. Recently, Par-4 was also found to form a complex with the dopamine D2 receptor (D2DR) in competition with the calcium-binding protein calmodulin, implicating Par-4 as an important regulatory component in normal dopamine signaling. Interestingly, mutant mice with disrupted Par-4/D2DR interaction demonstrated depressive-like behaviors, suggesting a potential role for Par-4 in both depression and schizophrenia. In this study, Par-4, D2DR and calmodulin protein levels were measured using semiquantitative Western blotting in postmortem temporal cortex in subjects with schizophrenia, major depression and bipolar disorder. Compared to normal controls, mean Par-4 levels appeared slightly lower in schizophrenia and bipolar disorder. However, in major depression, Par-4 was decreased by 67% compared to normal controls. No differences were found between any groups for calmodulin or for the D2DR 48 kDa band. The D2DR 98 kDa band was lower by 50% in the schizophrenia compared to control groups. Changes in the Par-4/D2DR signaling pathway represent a novel mechanism that may link apoptotic and dopamine signaling pathways in major depression and schizophrenia.
Glantz
Leisa A
LA
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Gilmore
John H
JH
Overstreet
David H
DH
Salimi
Kayvon
K
Lieberman
Jeffrey A
JA
Jarskog
L Fredrik
LF
D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000473:pathology*; D002147:Calmodulin / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000473:pathology*; D016708:Synaptophysin / Q000378:metabolism; D013702:Temporal Lobe / Q000187:drug effects / Q000378:metabolism*
D000928:Antidepressive Agents; D051017:Apoptosis Regulatory Proteins; D002147:Calmodulin; D017448:Receptors, Dopamine D2; D016708:Synaptophysin; C101296:prostate apoptosis response-4 protein