Selective Proteasomal Dysfunction in the Hippocampal CA1 Region after Transient Forebrain Ischemia

Abstract

Delayed neuronal death in the hippocampal CA1 region after transient forebrain ischemia may share its underlying mechanism with neurodegeneration and other modes of neuronal death. The precise mechanism, however, remains unknown. In the postischemic hippocampus, conjugated ubiquitin accumulates and free ubiquitin is depleted, suggesting impaired proteasome function. The authors measured regional proteasome activity after transient forebrain ischemia in male Mongolian gerbils. At 30 minutes after ischemia, proteasome activity was 40% of normal in the frontal cortex and hippocampus. After 2 hours of reperfusion, it had returned to normal levels in the frontal cortex, CA3 region, and dentate gyrus, but remained low for up to 48 hours in the CA1 region. Thus, the 26S proteasome was globally impaired in the forebrain during transient ischemia and failed to recover only in the CA1 region after reperfusion. The authors also measured 20S and 26S proteasome activities directly after decapitation ischemia (at 5 and 20 minutes) by fractionating the extracts with glycerol gradient centrifugation. Without adenosine triphosphate (ATP), only 20S proteasome activity was detected in extracts from both the hippocampus and frontal cortex. When the extracts were incubated with ATP in an ATP-regenerating system, 26S proteasome activity recovered almost fully in the frontal cortex but only partially in the hippocampus. Thus, after transient forebrain ischemia, ATP-dependent reassociation of the 20S catalytic and PA700 regulatory subunits to form the active 26S proteasome is severely and specifically impaired in the hippocampus. The irreversible loss of proteasome function underlies the delayed neuronal death induced by transient forebrain ischemia in the hippocampal CA1 region.

p53 Potentiates Hippocampal Neuronal Death Caused by Global Ischemia

“…However, persistent translational inhibition is a well-known phenomenon after transient ischemia in irreversibly injured neurons (Paschen, 2003;MacManus et al, 2004), suggesting that de novo synthesis of p53 protein from mRNA is unlikely, though not completely excluded. However, p53 is a short-lived protein, and its cellular level is regulated by degradation through the ubiquitin-proteasome pathway, which is severely impaired after global ischemia in the hippocampus, as we reported previously (Asai et al, 2002). Thus, it seems reasonable to assume that global ischemia increases the p53 protein level in vulnerable hippocampal neurons, presumably due to impaired degradation pathway.…”

Oxidative Stress Transiently Decreases the IKK Complex (IKKα, β, and γ), an Upstream Component of NF-κB Signaling, after Transient Focal Cerebral Ischemia in Mice

“…In cerebral ischemia in vivo, multiubiquitin chains persistently increased in the area where neurons are destined to die, and accumulation of multiubiquitin is caused by proteasomal dysfunction. The increase in inappropriate multiubiquitin proteins may aggravate apoptotic neuronal cell death after cerebral ischemia (Ide et al, 1999;Asai et al, 2002). Phosphorylated IkBa also Figure 5 SOD1 prevents increases in superoxide production and ubiquitinated protein after transient focal cerebral ischemia (tFCI).…”

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…Furthermore, it was shown that proteasomes are disassembled after an episode of global brain ischemia, partially because of ATP depletion (Fig. 4) (Asai et al, 2002). It remains to be determined why the ATP-dependent reassembly of 26S proteasome is selectively impaired in the hippocampal CA1 region.…”

“…In fact, transient global brain ischemia impairs 26S proteasome function by promoting proteasome disassembly, both in rats (Ge et al, 2007) and gerbils (Kamikubo and Hayashi, 1996;Asai et al, 2002). However, while the 26S proteasome activity recovers in many regions after reperfusion (e.g.…”

“…However, while the 26S proteasome activity recovers in many regions after reperfusion (e.g. CA3, dentate gyrus, and frontal cortex), in more vulnerable areas, such as CA1 region of the hippocampus, the 19S and 20S proteasomes do not fully reassociate, and the proteasome is irreversibly inhibited (Asai et al, 2002). A time-dependent decrease in proteasome activity has also been detected in ipsilateral cortex and hippocampus during 1-24 h reperfusion after transient focal ischemia , and this downregulation of proteasome activity was partly attributed to oxidative stress .…”