Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors used mRNA differential display to identify genes whose expression levels are altered in the adult rat hippocampus 24 hours after global ischemia. At this time after challenge, the basic helix-loop-helix transcription factor, SEF-2, and the 26S proteasome complex subunit, p112, were identified as genes whose expression levels are decreased and increased, respectively, in the hippocampus. To determine the spatial and temporal patterns of expression change for each gene, the authors antisense in situ hybridization to paired brain sections of sham-operated and global ischemia-challenged rats at 6, 12, and 24 hours after reperfusion SEF-2 expression was not significantly altered from that of sham-operated controls in any hippocampal subfield at or before 12 hours after challenge. At 24 hours after ischemia, however, SEF-2 expression levels were significantly diminished in the vulnerable CA1 subfield, but not in the less vulnerable CA3 or dentate granule cell subfields. The proteasome p112 subunit gene displayed no change in expression levels at 6 hours after insult; however, an elevated expression was observed at 12 hours after challenge in the dentate granule cell subfield. By 24 hours after challenge, p112 expression was significantly elevated in both the CA1 and dentate granule cell subfields. These results demonstrate that a member of the basic helix-loop-helix family of transcription factors, SEF-2, and the major subunit of the 26S proteasome complex, p112, display altered gene expression in the hippocampus after transient cerebral ischemia.
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PMID:Altered expression levels of SEF-2 and p112 in the rat hippocampus after transient cerebral ischemia: identification by mRNA differential display. 1019 13

The ubiquitin-proteasome protein degradation pathway is crucial in controlling intracellular levels of a variety of short-lived proteins and maintaining cellular growth and metabolism. In a previous study, we showed the accumulation of conjugated ubiquitin in CA1 neurons of the gerbil after 5 min of forebrain ischemia (; ). The accumulation of conjugated ubiquitin may reflect proteasome malfunction. In the present study, we investigated the effects of proteasome inhibitors on primary neuronal cultures to determine whether proteasomal malfunction induces neuronal death. When carbobenzoxy-Leu-Leu-Leu-aldehyde or lactacystin, two different types of proteasome inhibitors, were separately used to suppress proteasome activity, we observed induction of apoptotic neuronal cell death in both cases. During the apoptotic process, mitochondrial membrane potential was disrupted, cytochrome-c was released from mitochondria into the cytosol, and caspase-3-like proteases were activated. Apoptosis was inhibited by pretreatment with acetyl-aspartyl-glutamyl-valyl-aspart-1-aldehyde or overexpression of Bcl-x/(L). These results demonstrated that suppression of proteasome function induces neuronal apoptosis via the release of cytochrome c from mitochondria and activation of caspase-3-like proteases.
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PMID:Proteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons. 1062 3

It has been recently demonstrated that ubiquitin-proteasome-mediated proteolysis is required for long-term synaptic facilitation in Aplysia. Here we show that the hippocampal blockade of this proteolytic pathway is also required for the formation of long-term memory in the rat. Bilateral infusion of lactacystin, a specific proteasome inhibitor, to the CA1 region caused full retrograde amnesia for a one-trial inhibitory avoidance learning when given 1, 4 or 7h, but not 10 h, after training. Proteasome inhibitor I produced similar effects. In addition, inhibitory avoidance training resulted in an increased ubiquitination and 26S proteasome proteolytic activity and a decrease in the levels of IkappaB, a substrate of the ubiquitin-proteasome cascade, in hippocampus 4 h after training. Together, these findings indicate that the ubiquitin-proteasome cascade is crucial for the establishment of LTM in the behaving animal.
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PMID:The ubiquitin-proteasome cascade is required for mammalian long-term memory formation. 1186 Apr 77

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.
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PMID:Selective proteasomal dysfunction in the hippocampal CA1 region after transient forebrain ischemia. 1204 69

The clinical and neuropathological features in the P301L tauopathy have been described in several kindreds. In this study, we present findings in two previously unreported patients, evaluated both genetically, neuropathologically, and with multiparametric confocal immunofluorescence. The patients were female, with age 65 and 75 years old, respectively. Both exhibited clinical symptoms of frontotemporal dementia (FTD). Marked atrophy of the frontal and temporal lobes with moderate atrophy of the remaining cerebral and brain stem structures was present. The substantia nigra was pale. The atrophic neocortical regions exhibited neuronal loss, marked gliosis, status spongiosus, and occasional ballooned neurons. By light microscopy, the most striking findings were argyrophilic perinuclear rings, frequently with an attached small inclusion (mini Pick-like body), especially prominent in dentate granule cells, entorhinal and temporal cortices, and to a lesser extent in CA1. These structures were immunopositive for tau protein (Tau-2, AT-8, PHF-1, MC-1). Numerous astrocytic plaques, tuft-shaped astrocytes, coiled bodies, and dystrophic neurites were also present. Confocal immunofluorescence with a P301L-specific antibody directly demonstrated the presence of the mutated protein in the PHF-1 positive aggregates. The mutated tau protein (4-repeat tau) was detected in the mini Pick-like bodies, indicating an important biochemical difference between these inclusions and classical Pick bodies (3-repeat tau). Additionally, since 4-repeat tau protein is not normally present in dentate granule cells, this result also suggests an abnormality in the mRNA splicing mechanisms. The structural features of the involvement of proteolytic systems in this tauopathy were assessed by immunohistochemistry for the active form of calpain II (C-27) and ubiquitin. Colocalization of PHF-1 positive aggregates with C-27 points to the possible involvement of calpain in tau protein hyperphosphorylation. Absence of immunostaining for ubiquitin indicates possible dysfunction of the ubiquitin-proteasome system in this tauopathy.
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PMID:P301L tauopathy: confocal immunofluorescence study of perinuclear aggregation of the mutated protein. 1212 82

The present study examined the changes in 26S proteasome activity and the signal molecule mechanism regulating 26S proteasome activity in long term potentiation (LTP) in rat hippocampal slices. The results are as follows: 26S proteasome activity was 190+/-14.3 cpm/(100 microg.2 h) before tetanus, a significant increase in 26S proteasome activity (273+/-18.3 cpm/(100 microg.2 h) was found 10 min after tetanus, when the slope of fEPSP was markedly increased. Interestingly, 26S proteasome activity returned to baseline level (210+/-12.8 cpm/(100 microg.2 h) 60 min after tetanus. Moreover, the N-methyl-D-aspartate (NMDA) receptor inhibitor AP-5, which blocked LTP, prevented the increase in the 26S proteasome activity. The results suggest that NMDA receptors contribute to the transient increase in 26S proteasome activity during induction of LTP in the hippocampal CA1 region.
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PMID:[Relationship between hippocampal long term potentiation induction and activity of 26S proteasome]. 1469 80

The mechanisms underlying neurologic deficits and delayed neuronal death after ischemia are not fully understood. In the present study, we report that transient cerebral ischemia induces accumulation of ubiquitinated proteins (ubi-proteins) in postsynaptic densities (PSDs). By immunoelectron microscopy, we demonstrated that ubi-proteins were highly accumulated in PSD structures after ischemia. On Western blots, ubi-proteins were markedly increased in purified PSDs at 30 minutes of reperfusion, and the increase persisted until cell death in the CA1 region after ischemia. In the resistant DG area, however, the changes were transient and significantly less pronounced. Deposition of ubi-proteins in PSDs after ischemia correlates well with PSD structural damage in the CA1 region as viewed by electron microscopy. These results suggest that the ubiquitin-proteasome system fails to repair and remove damaged proteins in PSDs. The changes may demolish synaptic neurotransmission, contribute to neurologic deficits, and eventually lead to delayed neuronal death after transient cerebral ischemia.
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PMID:Protein ubiquitination in postsynaptic densities after transient cerebral ischemia. 1554 15

We studied the distribution of the ubiquitin-specific protease Usp9x in mouse brain as it relates to the potential role of ubiquitin proteasome system in synaptic plasticity. Usp9x is the mouse homolog of faf, known for its function in synaptic development in Drosophila. In adults, high levels of expression of Usp9x protein were found in layer V of neocortex, Purkinje cells in cerebellum, and specific hippocampal subfields. In hippocampal pyramidal cells, Usp9x expression was higher in CA3 than in CA1. This regional specificity was detected at postnatal day 22 but not at postnatal day 15. In adult mice, the CA1-CA3 difference was partially accounted for by a difference in the level of Usp9x mRNA, suggesting that transcription of Usp9x was differentially regulated between hippocampal subfields. Two synaptic marker proteins, synaptotagmin and spinophilin, were both more abundant in the striatum oriens of CA3 than in the similar region of CA1, correlating with the distribution of Usp9x, a result compatible with a role for Usp9x in synaptic development in mouse hippocampus. Ube1x, the enzyme responsible for the initial step in ubiquitin conjugation, was preferentially concentrated in the dendrites of the CA1 neurons instead of the CA3 neurons, suggesting a reciprocal relationship between ubiquitin conjugation and deubiquitination in CA3 and CA1. This spatial and temporal specificity in expression of Usp9x and Ube1x protein raises interesting questions about the roles of these ubiquitin enzymes in the differential functions of CA1 and CA3.
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PMID:Spatially and temporally specific expression in mouse hippocampus of Usp9x, a ubiquitin-specific protease involved in synaptic development. 1572 17

Expression of synaptic plasticity involves the translation of mRNA into protein and, probably, active protein degradation via the proteasome pathway. Here, we report on the rapid activation of synthesis and degradation of a probe protein with the induction of long-term potentiation (LTP) in the hippocampal Schaffer collateral CA1 pathway. The proteasome inhibitor MG132 significantly reduced the field EPSP slope potentiation and LTP maintenance without acutely affecting basal synaptic transmission. To visualize protein dynamics, CA1 pyramidal cells of hippocampal slices were transfected with Semliki Forest virus particles expressing a recombinant RNA. This RNA contained the coding sequence for a degradable green fluorescence protein with a nuclear localization signal (NLS-d1EGFP) followed by a 3'- untranslated region dendritic targeting sequence. NLS-d1EGFP fluorescence remained stable in the low-frequency test stimulation but increased with LTP induction in the cell body and in most dendritic compartments of CA1 neurons. Applying anisomycin, a protein synthesis inhibitor, caused NLS-d1EGFP levels to decline; a proteasome inhibitor MG132 reversed this effect. In the presence of anisomycin, LTP induction accelerated the degradation of NLS-d1EGFP. When both inhibitors were present, NLS-d1EGFP levels remained unaffected by LTP induction. Moreover, LTP-induced acceleration of NLS-d1EGFP synthesis was blocked by rapamycin, which is consistent with the involvement of dendritic mammalian target of rapamycin in LTP-triggered translational activity. Our results clearly demonstrate that LTP induction not only leads to a rapid increase in the rate of protein synthesis but also accelerates protein degradation via the proteasome system.
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PMID:Involvement of protein synthesis and degradation in long-term potentiation of Schaffer collateral CA1 synapses. 1667 70

Brain-pancreas relative protein (BPRP) is a novel protein that we found in our laboratory. Previously we demonstrated that it is involved in ischemia and depression. In light of the putative association between diabetes and clinical depression, and the selective expression of BPRP in brain and pancreas, the present study examined whether BPRP levels are affected by induction of diabetes by alloxan injection in rats and exposure to high glucose levels in PC12 cells. Western blot and immunohistochemical analyses revealed that BPRP levels were decreased in the hippocampal CA1 neurons of diabetic rats 4 and 8 weeks post-alloxan injection and in PC12 cells 48 h after exposure to high concentrations of glucose. BPRP protein levels were not affected by osmolarity control treatments with mannitol. Follow-up pharmacological experiments in PC12 cells revealed that glucose-induced BPRP down-regulation was markedly attenuated by the calpain inhibitors N-acetyl-Leu-Leu-norleucinal (ALLN) or calpeptin, but not the proteasome-specific inhibitor carbobenzoxy-Leu-Leu-leucinal (MG132). The ability of calpain inhibitors to specifically counter the effects of high glucose exposure on BPRP levels further suggests that BPRP and calpain activity may contribute to diabetes complications in the central nervous system.
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PMID:Down-regulation of brain-pancreas relative protein in diabetic rats and by high glucose in PC12 cells: prevention by calpain inhibitors. 1821 79


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