ER stress is the initial response to polyglutamine toxicity in PC12 cells.
Persistent endoplasmic reticulum (ER) stress and impairment of the ubiquitin-proteasome system (UPS) cause neuronal cell death. However, the relationship between these two phenomena remains controversial. In our current study, we have utilized an expanded polyglutamine fusion protein (polyQ81) expression system in PC12 cells to further examine the involvement of ER stress and UPS impairment in cell death. The expression of polyQ81-induced ER stress and cell death. PolyQ81 also induced the activation of c-Jun N-terminal kinase (JNK) and caspase-3 and an increase in polyubiquitin immunoreactivity, suggesting UPS impairment. ER stress was induced prior to the accumulation of polyubiquitinated proteins. Low doses of lactacystin had almost similar effects on cell viability and on the activation of JNK and caspase-3 between normal cells and polyQ81-expressing cells. These results suggest that ER stress mediates polyglutamine toxicity prior to UPS impairment during the initial stages of these toxic effects.
Nakayama
Hitoshi
H
Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara 634-8521, Japan. Electronic address: hitoshin@naramed-u.ac.jp.
Hamada
Masashi
M
Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and High Technology Research Center (HRC), Kansai University, Suita, Osaka 564-8680, Japan.
Fujikake
Nobuhiro
N
Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Nagai
Yoshitaka
Y
Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Zhao
Jing
J
Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara 634-8521, Japan.
Hatano
Osamu
O
Department of Anatomy, Nara Medical University School of Medicine, Kashihara, Nara 634-8521, Japan.
Shimoke
Koji
K
Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and High Technology Research Center (HRC), Kansai University, Suita, Osaka 564-8680, Japan.
Isosaki
Minoru
M
Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara 634-8521, Japan.
Yoshizumi
Masanori
M
Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara 634-8521, Japan.
Ikeuchi
Toshihiko
T
Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and High Technology Research Center (HRC), Kansai University, Suita, Osaka 564-8680, Japan.
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D017510:Protein Folding; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D011993:Recombinant Fusion Proteins; D025821:Polyubiquitin; C067713:lactacystin; C097188:polyglutamine; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine