Title:Endoplasmic Reticulum Stress and Bipolar Disorder - Almost Forgotten Therapeutic Drug Targets in the Unfolded Protein Response Pathway Revisited
Volume: 15
Issue: 4
Author(s): Susanne A. Bengesser, Robert Fuchs, Nina Lackner, Armin Birner, Bernd Reininghaus, Nathalie Meier-Allard, Anika Stracke, Hans-Peter Kapfhammer, Eva Z. Reininghaus and Sandra Wallner-Liebmann
Affiliation:
Keywords:
Bipolar disorder, endoplasmic reticulum, endoplasmic reticulum stress, unfolded protein response, lithium,
valproate.
Abstract: Bipolar Disorder (BD) is characterized by recurring mood swings, which are not completely understood yet. So
far, it is an accepted theory that multiple factors contribute to pathogenesis of BD according to the vulnerability-stressmodel.
This model combines on the one hand biological predisposing vulnerability, and on the other hand several chronic
and acute stressful negative events as underlying mechanisms of BD. Recently, ER (Endoplasmic Reticulum) stress
reached the spotlight of BD research again. The expression of the chaperone BiP (syn. GRP78/glucose-regulated protein,
78kDa), which is highly expressed in the Endoplasmic Reticulum (ER), is upregulated by different kinds of mood
stabilizers. These results implied that the ER, an organelle which is prone towards different kinds of cellular stress, might
be involved in the pathophysiology of BD. This hypothesis was further strengthened by hypothesis driven genetic
association studies, which showed significant association of BiP promotor polymorphisms with BD. Also other ER-stress
associated genes like XBP1 (X-box binding protein 1) or GRP94 (glucose-regulated protein, 94kDa, synonym for heat
shock protein HSP90B1) were recently linked to BD in hypothesis driven gene association studies. In addition to the
proteins mentioned before, our review focuses on further UPR (Unfolded Protein Response) related proteins associated
with BD and raises the hypothesis that ER-stress may represent a common interface between BD and obesity which is
overrepresented in BD patients. Finally, members of the UPR pathway are discussed as putative targets for mood
stabilizers.