Aberrant endoplasmic reticulum stress response in lymphoblastoid cells from patients with bipolar disorder.
Impaired endoplasmic reticulum (ER) stress response has been suggested as a possible pathophysiological mechanism of bipolar disorder (BD). The expression of ER stress-related genes, spliced form or unspliced form of XBP1, GRP78 (HSPA5), GRP94 (HSP90B1), CHOP (DDIT3), and calreticulin (CALR), were examined in lymphoblastoid cells derived from 59 patients with BD and 59 age- and sex-matched control subjects. Basal mRNA levels and induction by 4 h or 12 h of treatment with two ER stressors, thapsigargin or tunicamycin, were examined using real-time quantitative reverse transcription-polymerase chain reaction. Induction of the spliced form of XBP1 as well as total XBP1 by thapsigargin was significantly attenuated in patients with BD. Induction of GRP94 by thapsigargin was also decreased in the BD group. A haplotype of GRP94, protective against BD, exhibited significantly higher GRP94 expression upon ER stress. This report confirms and extends earlier observations of impaired ER stress response in larger samples of lymphoblastoid cell lines derived from BD patients. Altered ER stress response may play a role in the pathophysiology of BD by altering neural development and plasticity.
Hayashi
Akiko
A
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Japan.
Kasahara
Takaoki
T
Kametani
Mizue
M
Toyota
Tomoko
T
Yoshikawa
Takeo
T
Kato
Tadafumi
T
D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000235:genetics* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008214:Lymphocytes / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D017510:Protein Folding; D011569:Psychiatric Status Rating Scales; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D008565:Membrane Proteins; C018551:glucose-regulated proteins; D014415:Tunicamycin; D012313:RNA; D019284:Thapsigargin