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)

One of the main components of the senile plaques in brain tissue from patients with Alzheimer's disease is the beta-amyloid peptide. This peptide is proteolytically cleaved from the amyloid precursor protein by the action of at least two proteases, a beta-secretase which generates the N-terminus and a gamma-secretase which generates the C-terminus. Neither of these proteases have been identified. To identify proteases that are candidates for the gamma-secretase we synthesized a small fluorescent peptide substrate containing the amino acids comprising the C-terminus of the longest beta-amyloid peptide identified. This substrate is hydrolyzed by a single activity in homogenates from both cells and brain tissue and we have demonstrated that this activity is the multicatalytic enzyme or proteasome. Furthermore, using specific inhibitors, we have demonstrated that the fluorescent substrate is hydrolyzed by the chymotrypsin-like activity of the multicatalytic enzyme.
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PMID:Identification of the multicatalytic enzyme as a possible gamma-secretase for the amyloid precursor protein. 794 79

The beta-amyloid protein (Abeta) is derived by proteolytic processing of the amyloid protein precursor (APP). Cleavage of APP by beta-secretase generates a C-terminal fragment (APP-CTFbeta), which is subsequently cleaved by gamma-secretase to produce Abeta. The aim of this study was to examine the cleavage of APP-CTFbeta by gamma-secretase in primary cortical neurons from transgenic mice engineered to express the human APP-CTFbeta sequence. Neurons were prepared from transgenic mouse cortex and proteins labelled by incubation with [35S]methionine and [35S]cysteine. Labelled APP-CTFbeta and Abeta were then immunoprecipitated with a monoclonal antibody (WO2) specific for the transgene sequences. Approximately 30% of the human APP-CTFbeta (hAPP-CTFbeta) was converted to human Abeta (hAbeta), which was rapidly secreted. The remaining 70% of the hAPP-CTFbeta was degraded by an alternative pathway. The cleavage of hAPP-CTFbeta to produce hAbeta was inhibited by specific gamma-secretase inhibitors. However, treatment with proteasome inhibitors caused an increase in both hAPP-CTFbeta and hAbeta levels, suggesting that the alternative pathway was proteasome-dependent. A preparation of recombinant 20S proteasome was found to cleave a recombinant cytoplasmic domain fragment of APP (APPcyt) directly. The study suggests that in primary cortical neurons, APP-CTFbeta is degraded by two distinct pathways, one involving gamma-secretase, which produces Abeta, and a second major pathway involving direct cleavage of APP-CTFbeta within the cytoplasmic domain by the proteasome. These results raise the possibility that defective proteasome function could lead to an increase in Abeta production in the AD brain.
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PMID:The C-terminal fragment of the Alzheimer's disease amyloid protein precursor is degraded by a proteasome-dependent mechanism distinct from gamma-secretase. 1160 95

BACE457 is a recently identified pancreatic isoform of human beta-secretase. We report that this membrane glycoprotein and its soluble variant are characterized by inefficient folding in the ER, leading to proteasome-mediated ER-associated degradation (ERAD). Dissection of the degradation process revealed that upon release from calnexin, extensively oxidized BACE457 transiently entered in disulfide-bonded complexes associated with the lumenal chaperones BiP and protein disulfide isomerase (PDI) before unfolding and dislocation into the cytosol for degradation. BACE457 and its lumenal variant accumulated in disulfide-bonded complexes, in the ER lumen, also when protein degradation was inhibited. The complexes were disassembled and the misfolded polypeptides were cleared from the ER upon reactivation of the degradation machinery. Our data offer new insights into the mechanism of ERAD by showing a sequential involvement of the calnexin and BiP/PDI chaperone systems. We report the unexpected transient formation of covalent complexes in the ER lumen during the ERAD process, and we show that PDI participates as an oxidoreductase and a redox-driven chaperone in the preparation of proteins for degradation from the mammalian ER.
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PMID:Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER. 1211 63

The beta-amyloid protein (Abeta) is derived by proteolytic processing of the amyloid protein precursor (APP). Cleavage of APP by beta-secretase generates a C-terminal fragment (APP-CTFbeta), which is subsequently cleaved by gamma-secretase to produce Abeta. Our previous studies have shown that the proteasome can cleave the C-terminal cytoplasmic domain of APP. To identify proteasome cleavage sites in APP, two peptides homologous to the C-terminus of APP were incubated with recombinant 20S proteasome. Cleavage of the peptides was monitored by reversed phase high-performance liquid chromatography and mass spectrometry. Proteasome cleaved the APP C-terminal peptides at several sites, including a region around the sequence YENPTY that interacts with several APP-binding proteins. To examine the effect of this cleavage on Abeta production, APP-CTFbeta and mutant forms of APP-CTFbeta terminating on either side of the YENPTY sequence were expressed in CHO cells. Truncation of APP-CTFbeta on the N-terminal side of the YENPTY sequence at residue 677 significantly decreased the amount of Abeta produced, whereas truncation on the C-terminal side of residue 690 had little effect. The results suggest that proteasomal cleavage of the cytosolic domain of APP at the YENPTY sequence decreases gamma-secretase processing, and consequently inhibits Abeta production. Therefore, the proteasome-dependent trafficking pathway of APP may be a valid therapeutic target for altering Abeta production in the Alzheimer's disease brain.
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PMID:Proteasome-mediated degradation of the C-terminus of the Alzheimer's disease beta-amyloid protein precursor: effect of C-terminal truncation on production of beta-amyloid protein. 1459 14

The amyloid beta protein (Abeta) is derived from beta-amyloid precursor protein (APP). Cleavage of APP by beta-secretase generates a C-terminal fragment (APPCTFbeta or C99), which is subsequently cleaved by gamma-secretase to produce Abeta. BACE (or BACE1), the major beta-secretase involved in cleaving APP, has been identified as a Type 1 membrane-associated aspartyl protease. In this study, we found that treatment with proteasome inhibitors resulted in an increase in APP C99 levels, suggesting that APP processing at the beta-secretase site may be affected by the ubiquitin-proteasome pathway. To investigate whether the degradation of BACE is mediated by the proteasome pathway, cells stably transfected with BACE were treated with lactacystin. We found that BACE protein degradation was inhibited by lactacystin in a time- and dose-dependent manner. Non-proteasome protease inhibitors had no effect on BACE degradation. BACE protein is ubiquitinated. Furthermore, lactacystin increased APP C99 production and Abeta generation. Our data demonstrate that the degradation of BACE proteins and APP processing are regulated by the ubiquitin-proteasome pathway.
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PMID:Degradation of BACE by the ubiquitin-proteasome pathway. 1528 51

Deposition of amyloid beta protein in the brain is the major pathological feature of Alzheimer's disease. Amyloid beta protein is generated from beta-amyloid precursor protein by beta-secretase and gamma-secretase. Proteolytic processing of amyloid precursor protein at the beta site by BACE1 is essential to generate amyloid beta protein. BACE1, the major beta-secretase involved in cleaving amyloid precursor protein, has been identified as a type 1 membrane-associated aspartyl protease. In this study, we found that BACE1 gene expression is controlled by a TATA-less promoter. BACE1 gene expression is tightly regulated at the transcriptional level and the transcription factor Sp1 plays an important role in regulation of BACE1 to process amyloid precursor protein generating amyloid beta protein. Furthermore, we found that BACE1 protein is ubiquitinated, and the degradation of BACE1 proteins and amyloid precursor protein processing are regulated by the ubiquitin-proteasome pathway.
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PMID:BACE1 gene expression and protein degradation. 1568

The human amyloid precursor protein (APP) is processed by the nonamyloidogenic and the amyloidogenic catabolic pathways. The sequential cleavage of APP by the beta- and gamma-secretase activities, known as the amyloidogenic processing of APP, leads to the formation of the amyloid-beta peptide (Abeta). Abeta is the main constituent of the amyloid core of senile plaques, a typical hallmark of Alzheimer's disease. In addition to secretases, other cellular proteolytic activities, like the proteasome, might participate in the metabolism of APP. We investigated the consequence of proteasome inhibition on the amyloidogenic processing of human APP. CHO cells and primary cultures of rat cortical neurons expressing human APP or a protein corresponding to its beta-cleaved C-terminal fragment (C99) were treated with lactacystin, an irreversible inhibitor of the chymotrypsin-like activity of the proteasome. Lactacystin significantly decreased the level of Abeta produced from APP in both cellular models, whereas the production of Abeta from C99 was not affected. Lactacystin did not inhibit gamma-secretase activity but was found to inhibit the beta-cleavage of APP, leading to a proportional decrease in Abeta production. Although lactacystin did not inhibit the catalytic activity of recombinant BACE1, a decrease in neuronal beta-secretase activity was measured after treatment with lactacystin.
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PMID:Lactacystin decreases amyloid-beta peptide production by inhibiting beta-secretase activity. 1694 95

Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease and are known to increase amyloid-beta42 (Abeta42) production as well as to promote apoptosis. We have recently reported that intracellular Abeta42 activates p53 mRNA expression and promotes p53-dependent apoptosis. Here, we examined the p53 mRNA and protein levels in cells transfected with wild-type and I143T/G384A mutant PS1 genes. Although the baseline p53 mRNA levels remained unaltered, the p53 protein levels were significantly elevated in mutant PS1-transfected cells. Treatments with apoptosis-inducing agents induced significant elevation of the p53 protein but not p53 mRNA levels in mutant PS1-transfected cells. Treatment with a beta-secretase inhibitor and gamma-secretase inhibitor decreased the intracellular Abeta levels in amyloid-beta protein precursor (AbetaPP) and PS1-double transfected cells, and restrained upregulation of the p53 protein levels in the mutant PS1-transfected cells. Also, we found that proteasome activity was decreased in mutant PS1-transfected cells compared to wild-type PS1-transfected cells. Proteasome activity was further decreased in AbetaPP/PS1-double transfected cells. Taken together, p53-dependent apoptosis upregulated by the I143T/G384A mutant PS1 gene may be associated, at least in part, with intracellular Abeta and proteasome impairment.
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PMID:Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors. 1927 51

Previous studies have demonstrated that ischemic stroke increases beta-amyloid (Abeta) production by increasing beta-secretase (BACE1) through activation of caspase-3, and stimulates generation of mutant ubiquitin (UBB(+1)) in rat brains. In this study, we examined whether caspase-3 activation participates in the regulation of UBB(+1) generation and UBB(+1)-mediated BACE1 stability in ischemic injured brains. The results showed that UBB(+1) and activated caspase-3-immunopositive-stained cells were time dependently increased in the ipsilateral striatum of rat brains after middle cerebral artery occlusion. UBB(+1)-immunopositive cells could be co-stained with caspase-3, Abeta (UBB(+1)-Abeta), and BACE1 (UBB(+1)-BACE1). BACE1 protein could also be pulled down by immunoprecipitation with UBB(+1) antibody. Z-DEVD-FMK (DEVD), a caspase-3 inhibitor, significantly decreased the level of UBB(+1) protein and the number of UBB(+1)-Abeta and UBB(+1)-BACE1 double-stained cells in the ischemic striatum, as well as the level of UBB(+1)/BACE1 protein complex. We conclude that activation of caspase-3 might be upstream of UBB(+1) formation and that excessive UBB(+1) could bind to BACE1 and increase the stability of BACE1, thereby increasing Abeta in ischemic injured brains. These results suggest new biological and pathological effects of caspases and regulation of the ubiquitin-proteasome system in the brain. Our results provide new therapeutic targets to prevent further neurodegeneration in patients after stroke.
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PMID:Mutant ubiquitin-mediated beta-secretase stability via activation of caspase-3 is related to beta-amyloid accumulation in ischemic striatum in rats. 1984 37

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