Lack of p53 delays apoptosis, but increases ubiquitinated inclusions, in proteasomal inhibitor-treated cultured cortical neurons.
Proteasomal dysfunction may contribute to neurodegenerative diseases; however, its effects on primary neurons are largely unknown. We have previously reported that pharmacological proteasomal inhibition leads to apoptosis and cytoplasmic ubiquitinated inclusions in primary rat cortical neurons. In cell lines the transcription factor p53 is regulated by the proteasome and in some cases it mediates death following proteasomal inhibition. It is unclear, however, if this is the case in primary neurons. Here we show in proteasome inhibitor-treated cortical neurons an early increase of p53 levels, accompanied by nuclear translocation. At later time points p53 is found sequestered within ubiquitinated inclusions. Compared to controls, p53-deficient mouse neurons show delayed apoptosis, but increased numbers of inclusions, likely secondary to enhanced survival. We conclude that p53 plays a role in cortical neuron apoptosis induced by proteasomal inhibition and, despite the fact that it localizes to inclusions, it is not necessary for their formation.
Department of Neurology, Columbia University, Black Building Room 326, 650 W. 168 Street, New York, NY 10032, USA.
Paula
P
Dietrich
Hardy J
HJ
Rideout
Qiaohong
Q
Wang
Leonidas
L
Stefanis
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D002479:Inclusion Bodies / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D025801:Ubiquitin / Q000494:pharmacology
D009097:Multienzyme Complexes; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex