Role of p53 in neurotoxicity induced by the endoplasmic reticulum stress agent tunicamycin in organotypic slice cultures of rat spinal cord.
The endoplasmic reticulum (ER) is important for maintaining the quality of cellular proteins. Various stimuli can disrupt ER homeostasis and cause the accumulation of unfolded or misfolded proteins, i.e., a state of ER stress. Recently, ER stress has been reported to play an important role in the pathogenesis of neurological disorders such as cerebral ischemia and neurodegenerative diseases, but its involvement in the spinal cord diseases has not been fully discussed. We conducted this study using tunicamycin (Tm) as an ER stress inducer for rat spinal cord in organotypic slice culture, a system that we have recently established. Tm was shown to induce ER stress by increased expression of GRP78. The viability rate of spinal cord neurons decreased in a dose-dependent manner with Tm treatment, and dorsal horn interneurons were more vulnerable to Tm-induced neurotoxicity. A p53 inhibitor significantly increased the viability of dorsal horn interneurons, and immunofluorescence studies showed nuclear accumulation of p53 in the dorsal horns of Tm-treated spinal cord slices. These findings suggest that p53 plays an important role in the killing of dorsal horn interneurons by Tm. In contrast, motor neurons were not protected by the p53 inhibitor, suggesting that the role of p53 may vary between different cell types. This difference might be a clue to the mechanism of the stress-response pathway and might also contribute to the potential application of p53 inhibitors for the treatment of spinal cord diseases, including amyotrophic lateral sclerosis.
Tashiro
Jun
J
Department of Neurology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Hokkaido, Japan. jtashiro@med.hokudai.ac.jp
Kikuchi
Seiji
S
Shinpo
Kazuyoshi
K
Kishimoto
Riichiro
R
Tsuji
Sachiko
S
Sasaki
Hidenao
H
D000818:Animals; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D018832:Molecular Chaperones / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D009924:Organ Culture Techniques; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*; D014415:Tunicamycin / Q000633:toxicity*; D000091342:Endoplasmic Reticulum Chaperone BiP
D020126:Brefeldin A; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009498:Neurotoxins; D011500:Protein Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D014415:Tunicamycin; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP