protein folding and depression
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) (Wang et al. 1999). GRP78 is a member of the ER stress protein family that includes GRP94 and calreticulin, all of which function as Ca2+ 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 involved in the pathophysiology of mood disorders, perhaps as compensatory factors induced in response to stress-related neuronal damage. Further evidence for a role of neuroprotective proteins in mood disorders comes from recent reports of increased Bcl-2 levels, another neuroprotective anti-apoptotic factor, after treatment with mood stabilizers (Chen et al. 1999; Chen and Chuang 1999). To test the hypothesis that ER stress proteins may be important in the pathophysiology of mood disorders, we measured GRP78, GRP94 and calreticulin in postmortem samples of patients with mood disorders, schizophrenia and nonpsychiatric controls.
FK506 binding protein 5