Proteasome inhibition results in increased poly-ADP-ribosylation: implications for neuron death.
This study demonstrates the ability of proteasome inhibitors (lactacystin, MG 115, MG 132) adenosine diphosphate to induce a time- and dose-dependent increase in poly-ADP-ribosylation (PAR) in the neural PC6 cell line, a subclone of PC12 cells. Elevated levels of PAR contribute to the toxicity associated with impaired proteasome activity, based on the ability of PAR inhibitors to ameliorate the toxicity associated with the application of lactacystin, MG 115, and MG 132. Proteasome inhibitors induced the accumulation of PAR and neuron death in primary hippocampal neuron cultures, which were both ameliorated by treatment with PAR inhibitors. Together, these data indicate a role for increased PAR in the toxicity associated with proteasome inhibition, and suggest that inhibitors of PAR may provide neuroprotection in conditions where proteasome inhibition occurs.
Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, University of Kentucky Medical Center, Lexington, Kentucky.
J N
JN
Keller
W R
WR
Markesbery
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004622:Embryo, Mammalian; D006624:Hippocampus; D009097:Multienzyme Complexes / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley
D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D011065:Poly(ADP-ribose) Polymerases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex