Accumulation of phosphorylated neurofilaments and increase in apoptosis-specific protein and phosphorylated c-Jun induced by proteasome inhibitors.
The ubiquitin-proteasome system has been regarded as being important in the progression of neurodegenerative diseases, although its exact role remains uncertain. This in vitro study using PC12h cell cultures examined whether interference with the ubiquitin-proteasome system by proteasome inhibitors induces the neuropathological features of neurodegenerative diseases. Perikaryal accumulation of phosphorylated neurofilaments and an increase in c-Jun as well as phosphorylated form of c-Jun and apoptosis-specific protein were induced by the proteasome inhibitors lactacystin and N-carbobenzoxy-leucyl-leucyl-leucinal. These changes were not observed when only calpain was inhibited. The present study therefore suggests the possibility that a perturbation of the ubiquitin-proteasome system may be one of the causes that result in the development of neuropathological features. Additionally, activity assays showed that the proteasome inhibitor caused an increase in the activity of c-Jun N-terminal kinase (JNK/SAPK), which can phosphorylate neurofilaments and c-Jun, suggesting the possible involvement of JNK in phosphorylation of these proteins.
Masaki
R
R
Department of Anatomy, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Japan.
Saito
T
T
Yamada
K
K
Ohtani-Kaneko
R
R
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases; D007976:Leupeptins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D014452:Ubiquitins / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D016900:Neurofilament Proteins; D016755:Proto-Oncogene Proteins c-jun; D014452:Ubiquitins; C067713:lactacystin; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000469:Alkaline Phosphatase; D002154:Calpain; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine