Neuroscience 2002 Abstract
| Presentation Number: | 595.20 |
|---|---|
| Abstract Title: | Involvement of p53 in proteasome inhibition-induced neuronal death and inclusion formation. |
| Authors: |
Dietrich, P.*1
; Rideout , H. J.1
; Wang, Q.1
; Stefanis, L.1,2
1Neurology, Columbia University, New York, NY 2Pathology, Columbia University, New York, NY |
| Primary Theme and Topics |
Neurological and Psychiatric Conditions - Neurodegenerative Disorders -- Parkinsons DIsease: Models |
| Secondary Theme and Topics | Development<br />- Trophic Factors and Developmental Cell Death<br />-- Trophic factors and cell death |
| Session: |
595. Neurodegenerative disorders: Parkinson's disease--models IV Poster |
| Presentation Time: | Tuesday, November 5, 2002 4:00 PM-5:00 PM |
| Location: | Hall A2-B3 Y-14 |
| Keywords: | PARKINSON, APOPTOSIS, CASPASE, KNOCKOUT |
We have reported that proteasomal inhibition of cultured rat cortical neurons leads to accumulation of detergent-insoluble polyubiquitinated species, formation of cytoplasmic inclusions and apoptotic death (SFN 2001:195.17). Here we examine the involvement of the tumor suppressor p53 in this model. p53 is known to play a role in some, but not all, models of proteasomal inhibition-induced death in cell lines. Whether it is regulated by the proteasome in neurons, and whether it is involved in proteasome inhibition-induced neuronal death or inclusion formation is unknown. 4-8 hrs after application of the specific proteasomal inhibitor lactacystin to E18 cortical neurons, total p53 protein levels increase, and p53 immunoreactivity accumulates in the nucleus. 24-36 hrs after lactacystin application, p53 is found within cytoplasmic inclusions. To test the requirement of p53 in these processes, we derived neurons from p53 +/+, +/-, and -/- mice. We found that lactacystin-induced death was dose-dependently attenuated in the absence of p53. However, apoptosis, as evidenced by nuclear staining and caspase 3 activation, did occur in a delayed fashion in p53-/- neurons. Accumulation of polyubiquitinated species was not affected, whereas the percentage of neurons with cytoplasmic ubiquitinated inclusions increased in p53-/- mice, presumably because of enhanced survival. We conclude that p53 acts as a regulator of apoptosis, but it is not necessary for apoptotic death. Furthermore, it is not required for ubiquitinated inclusion formation, even though it accumulates within such inclusions.
Supported by APDA, PDF, Wellcome Burroughs, Matheson Foundation
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2002 Neuroscience Meeting Planner. Orlando, FL: Society for Neuroscience, 2002. Online.
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