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The Journal of Neuroscience, January 2, 2008, 28(1):50-59; doi:10.1523/JNEUROSCI.3474-07.2008

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Neurobiology of Disease
Ubiquitin–Proteasome-Mediated Synaptic Reorganization: A Novel Mechanism Underlying Rapid Ischemic Tolerance

Robert Meller,¹ Simon John Thompson,¹ Theresa Ann Lusardi,¹ Andrea Nicole Ordonez,¹ Michelle Dawn Ashley,¹ Veronica Jessick,¹ Weihzen Wang,¹ Daniel John Torrey,¹ David Clifford Henshall,^1,2 Philip R. Gafken,³ Julie Anne Saugstad,¹ Zhi-Gang Xiong,¹ and Roger Pancoast Simon¹

¹Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, ²Royal College of Surgeons Ireland, Dublin 2, Ireland, and ³Proteomics Facility, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109

Correspondence should be addressed to Robert Meller, Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232. Email: rmeller{at}downeurobiology.org

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 (gene-mediated) ischemic tolerance, the mechanisms underlying rapid (protein synthesis-independent) ischemic tolerance are relatively unknown. Here we describe 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.

Key words: ischemia; actin; NMDA; proteasome; dendritic spines; ubiquitin; ischemia

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Received March 23, 2007; revised Oct. 22, 2007; accepted Nov. 1, 2007.

Correspondence should be addressed to Robert Meller, Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232. Email: rmeller{at}downeurobiology.org

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