Ubiquitin-proteasome-mediated synaptic reorganization: A novel mechanism underlying rapid ischemic tolerance

Robert Meller, Simon John Thompson, Theresa Ann Lusardi, Andrea Nicole Ordonez, Michelle Dawn Ashley, Veronica Jessick, Weihzen Wang, Daniel John Torrey, David Clifford Henshall, Philip R. Gafken, Julie Anne Saugstad, Zhi Gang Xiong, Roger Pancoast Simon

Research output: Contribution to journalArticle

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Abstract

Ischemic tolerance is an endogenous neuroprotective mechanism in brain and other organs, whereby prior exposure to brief ischemia produces resilience to subsequent normally injurious ischemia. Although many molecular mechanisms mediate delayed (genemediated) ischemic tolerance, the mechanisms underlying rapid (protein synthesis-independent) ischemic tolerance are relatively unknown. Herewedescribe a novel mechanism for the induction of rapid ischemic tolerance mediated by the ubiquitin-proteasome system. Rapid ischemic tolerance is blocked by multiple proteasome inhibitors [carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), MG115 (carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal), and clasto-lactacystin-β-lactone]. A proteomics strategy was used to identify ubiquitinated proteins after preconditioning ischemia. We focused our studies on two actin-binding proteins of the postsynaptic density that were ubiquitinated after rapid preconditioning: myristoylated, alanine-rich C-kinase substrate (MARCKS) and fascin. Immunoblots confirm the degradation of MARCKS and fascin after preconditioning ischemia. The loss of actin-binding proteins promoted actin reorganization in the postsynaptic density and transient retraction of dendritic spines. This rapid and reversible synaptic remodeling reduced NMDA-mediated electrophysiological responses and renders the cells refractory to NMDA receptor-mediated toxicity. The dendritic spine retraction and NMDA neuroprotection after preconditioning ischemia are blocked by actin stabilization with jasplakinolide, as well as proteasome inhibition with MG132. Together these data suggest that rapid tolerance results from changes to the postsynaptic density mediated by the ubiquitin-proteasome system, rendering neurons resistant to excitotoxicity.

Original languageEnglish (US)
Pages (from-to)50-59
Number of pages10
JournalJournal of Neuroscience
Volume28
Issue number1
DOIs
StatePublished - Jan 2 2008

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Keywords

  • Actin
  • Dendritic spines
  • Ischemia
  • NMDA
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Meller, R., Thompson, S. J., Lusardi, T. A., Ordonez, A. N., Ashley, M. D., Jessick, V., Wang, W., Torrey, D. J., Henshall, D. C., Gafken, P. R., Saugstad, J. A., Xiong, Z. G., & Simon, R. P. (2008). Ubiquitin-proteasome-mediated synaptic reorganization: A novel mechanism underlying rapid ischemic tolerance. Journal of Neuroscience, 28(1), 50-59. https://doi.org/10.1523/JNEUROSCI.3474-07.2008