Increased Temporal Cortex ER Stress Proteins in Depressed Subjects Who Died by Suicide

Abstract

Regulation of ER stress proteins, such as the 78-kilodalton glucose regulated protein (GRP78) by chronic treatment with mood stabilizing drugs suggests that this family of proteins may be involved in the pathophysiology of mood disorders. Indeed, increased levels of GRP78, GRP94, and calreticulin, a third member of the ERCurrent theories of the pathophysiology of mood disorders suggest that prolonged increases in glucocorticoid levels, likely the result of prolonged environmental stress, lead to biochemical changes in cortical and limbic neurons that leave individuals vulnerable to depression (Duman et al. 1997). A number of studies have found evidence of neuronal atrophy and loss of hippocampal neurons in response to stress (Magarinos et al. 1996;Uno et al. 1989;Sapolsky et al. 1985), and a report of reduced hippocampal volumes in elderly patients with histories of depression suggests that analogous processes may occur in individuals with depression (Sheline et al. 1996). Some models of mood disorders (Hyman and Nestler 1996; Post 1992) have attempted to incorporate the notion of compensatory processes into an understanding of the pathophysiologic changes that occur in patients with mood disorders, but few studies have tested these notions empirically (Post 1992). Part of the difficulty has been identifying neuroprotective mechanisms that may be of relevance for mood disorders.Recently, we found that treatment with the mood stabilizing drugs, valproate and carbamazepine, increased expression of the 78-kilodalton glucose-regulated protein (GRP78) . GRP78 is a member of the ER stress protein family that includes GRP94 and calreticulin, all of which function as Ca 2 ϩ binding proteins and molecular chaperones to assist in the regulation of protein folding (Gething 1997). These proteins have neuroprotective properties, are induced by seizures and ischemic damage, and may be involved in Alzheimer's disease pathology (Yu et al. 1999;Lowenstein et al. 1994;Hamos et al. 1991).Increased expression of ER stress proteins by mood stabilizing drugs suggest that these proteins may be in- METHODS Postmortem brain tissue was obtained from the StanleyFoundation Neuropathology Consortium (4 groups of n ϭ 15 age-and sex-matched subjects, i.e., subjects with bipolar disorder (BD), subjects with Major Depressive Disorder (MDD), subjects with schizophrenia (SCZ), and non-psychiatric, non-neurologic comparison subjects) (Johnston et al. 1997). Details on dissection and clinical characteristics have been previously published (Dowlatshahi et al. 1998(Dowlatshahi et al. , 1999. Briefly, all medical records for psychiatric cases were reviewed by two psychiatrists. Diagnosis was determined according to DSM-IV criteria. If there was disagreement about the diagnosis, a third psychiatrist read the records. If a diagnosis could not be established, a family member was then interviewed. All interviewed relatives were first degree except for two (one aunt and one father-in-law). Similarly, a clinical interview was performed with a family member...

Luteolin Shows an Antidepressant-Like Effect via Suppressing Endoplasmic Reticulum Stress

“…23) In postmortem brain studies, increased levels of endoplasmic reticulum stress-related proteins such as GRP78, GRP94, and calreticulin have been found in the temporal cortex of subjects with major depressive disorder who died of suicide. 5) In corticosterone-treated animal depression models, increased levels of GRP78 and other endoplasmic reticulum stress-related proteins have been reported in the dentate gyrus and other region. 6,24) These reports suggest that neuronal cell death and endoplasmic reticulum stress may be involved in the pathogenesis of depression.…”

“…5) Furthermore, in a rodent depression model, endoplasmic reticulum stress-related proteins were increased and these were attenuated by an antidepressant. 6) Recently, we have reported that restraint stress increases in the expression of endoplasmic reticulum stress-related genes in the mouse brain.…”

Association analysis of HSP90B1 with bipolar disorder

“…The first evidence was detection of ER chaperones such as HSPA5, HSP90B1 and CALR as target genes of a mood stabilizer, valproate, using differential display (Wang et al 1999). Subsequently, increased expression of ER chaperones in the temporal cortex of depressed subjects who died by suicide was reported (Bown et al 2000). One microarray study using postmortem brain samples showed altered expression of HSP90B1 (gp96) in the bipolar disorder patients (Jurata et al 2004).…”

“…HSP90B1 expression is induced by treatment with valproate and lithium (Shao et al 2006) and its expression is altered in the postmortem brain of bipolar disorder patients (Bown et al 2000). The HSP90B1 gene is located on 12q23.3.…”

A point mutation at the calreticulin gene core promoter conserved sequence in a case of schizophrenia

“…calreticulin) that assist in the folding of proteins in the endoplasmic reticulum (ER) [Bown et al, 2000[Bown et al, , 2002Chen et al, 2000;Kim et al, 2005]. Calreticulin is a multifunctional protein that acts as a major Ca(2þ)-binding storage protein in the lumen of the ER.…”