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)

Peptide aldehyde inhibitors of the chymotrypsin-like activity of the proteasome (CLIP) such as N-acetyl-Leu-Leu-Nle-H (or ALLN) have been shown previously to inhibit the secretion of beta-amyloid peptide (A beta) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on A beta formation of a much wider range of peptide-based inhibitors of CLIP than published previously. The inhibitors tested included several peptide boronates, some of which proved to be the most potent peptide-based inhibitors of beta-amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress A beta formation from cells correlated extremely well with their potency as CLIP inhibitors. Thus, we conclude that the proteasome may be involved either directly or indirectly in A beta formation.
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PMID:Alzheimer's disease: correlation of the suppression of beta-amyloid peptide secretion from cultured cells with inhibition of the chymotrypsin-like activity of the proteasome. 1038 71

The proteasome is a multicatalytic complex involved in the degradation of polyubiquitinated proteins. Here we review the clues of a possible involvement of the proteasome in Alzheimer's disease neuropathology. Thus, we discuss the fact that the proteasome modulates the intracellular concentrations of presenilins 1 and 2. These two proteins, when mutated, appear responsible for most of early onset forms of Alzheimer's disease and this is thought to be due to the exacerbation of the pathogenic pathway of the maturation of the beta-amyloid precursor protein. Controlling presenilins concentrations could have drastic repercussions on cell physiology as suggested by the fact that proteasome inhibitors drastically potentiate the 'normal' or 'pathogenic' presenilins phenotype related with betaAPP processing. The possibility of considering the proteasome as a potential target for therapeutic intervention in Alzheimer's disease is discussed.
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PMID:Role of the proteasome in Alzheimer's disease. 1089 38

The amyloid beta-peptide (Abeta) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer's disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data do imply roles for both the toxic Abeta and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated that Abeta can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins. Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized that oxidatively modified Abeta might have a stronger (or weaker) inhibitory effect on the proteasome than does native Abeta. We therefore also investigated the proteasome inhibitory action of Abeta1-40 (a peptide comprising the first 40 residues of Abeta) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H2O2 modification of Abeta1-40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Abeta1-40 generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized protein substrates by human 20S proteasome. This interaction may contribute to certain pathological manifestations of Alzheimer's disease.
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PMID:4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease. 1113 Jan 84

The gamma-secretase cleavage is the last step in the generation of the beta-amyloid peptide (Abeta) from the amyloid precursor protein (APP). The Abeta precipitates in the amyloid plaques in the brain of Alzheimer's disease patients. The fate of the intracellular APP carboxy-terminal stub generated together with Abeta has been, in contrast, only poorly documented. The analogies between the processing of APP and other transmembrane proteins like SREBP and Notch suggests that this intracellular fragment could have important signalling functions. We demonstrate here that APP-C59 is rapidly degraded (half-life approximately 5 min) when overexpressed in baby hamster kidney cells or primary cultures of neurones by a mechanism that is not inhibited by endosomal/lysosomal or proteasome inhibitors. Furthermore, APP-C59 binds to the DNA binding protein Fe65, although this does not increase the half-life of APP-C59. Finally, we demonstrate that a fraction of APP-C59 becomes redistributed to the nuclear detergent-insoluble pellet, in which the transcription factor SP1 is also present. Overall our results reinforce the analogy between Notch and APP processing, and suggest that the APP intracellular domain, like the Notch intracellular domain, could have a role in signalling events from the plasma membrane to the nucleus.
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PMID:The amyloid precursor protein (APP)-cytoplasmic fragment generated by gamma-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture. 1155 91

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

The low density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional cell surface receptor that interacts through its cytoplasmic tail with adaptor and scaffold proteins that participate in cellular signaling. Its extracellular domain, like that of the signaling receptor Notch and of amyloid precursor protein (APP), is proteolytically processed at multiple positions. This similarity led us to investigate whether LRP, like APP and Notch, might also be cleaved at a third, intramembranous or cytoplasmic site, resulting in the release of its intracellular domain. Using independent experimental approaches we demonstrate that the cytoplasmic domain is released by a gamma-secretase-like activity and that this event is modulated by protein kinase C. Furthermore, cytoplasmic adaptor proteins that bind to the LRP tail affect the subcellular localization of the free intracellular domain and may regulate putative signaling functions. Finally, we show that the degradation of the free tail fragment is mediated by the proteasome. These findings suggest a novel role for the intracellular domain of LRP that may involve the subcellular translocation of preassembled signaling complexes from the plasma membrane.
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PMID:Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. 1190 44

Modifier of cell adhesion protein (MOCA; previously called presenilin [PS] binding protein) is a DOCK180-related molecule, which interacts with PS1 and PS2, is localized to brain areas involved in Alzheimer's disease (AD) pathology, and is lost from the soluble fraction of sporadic Alzheimer's disease (AD) brains. Because PS1 has been associated with gamma-secretase activity, MOCA may be involved in the regulation of beta-amyloid precursor protein (APP) processing. Here we show that the expression of MOCA decreases both APP and amyloid beta-peptide secretion and lowers the rate of cell-substratum adhesion. In contrast, MOCA does not lower the secretion of amyloid precursor-like protein (APLP) or several additional type 1 membrane proteins. The phenotypic changes caused by MOCA are due to an acceleration in the rate of intracellular APP degradation. The effect of MOCA expression on the secretion of APP and cellular adhesion is reversed by proteasome inhibitors, suggesting that MOCA directs nascent APP to proteasomes for destruction. It is concluded that MOCA plays a major role in APP metabolism and that the effect of MOCA on APP secretion and cell adhesion is a downstream consequence of MOCA-directed APP catabolism. This is a new mechanism by which the expression of APP is regulated.
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PMID:A novel mechanism for the regulation of amyloid precursor protein metabolism. 1209 89

Ageing research in Greece is well established. Research groups located in universities, research institutes or public hospitals are studying various and complementary aspects of ageing. These research activities include (a) functional analysis of Clusterin/Apolipoprotein J, studies in healthy centenarians and work on protein degradation and the role of proteasome during senescence at the National Hellenic Research Foundation; (b) regulation of cell proliferation and tissue formation, a nationwide study of determinants and markers of successful ageing in Greek centenarians and studies of histone gene expression and acetylation at the National Center for Scientific Research, Demokritos; (c) work on amyloid precursor protein and Presenilin 1 at the University of Athens; (d) oxidative stress-induced DNA damage and the role of oncogenes in senescence at the University of Ioannina; (e) studies in the connective tissue at the University of Patras; (f) proteomic studies at the Biomedical Sciences Research Center Alexander Fleming; (g) work on Caenorhabditis elegans at the Foundation for Research and Technology; (h) the role of ultraviolet radiation in skin ageing at Andreas Sygros Hospital; (i) follow-up studies in healthy elderly at the Athens Home for the Aged; and (j) socio-cultural aspects of ageing at the National School of Public Health. These research activities are well recognized by the international scientific community as it is evident by the group's very good publication records as well as by their direct funding from both European Union and USA. This article summarizes these research activities and discuss future directions and efforts towards the further development of the ageing field in Greece.
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PMID:Ageing research in Greece. 1217 74

The etiology of Alzheimer's disease (AD) is not well understood. Etiologic factors, chronic inflammatory reactions, oxidative and nitrosylative stresses and high cholesterol levels are thought to be important for initiating and promoting neurodegenerative changes commonly found in AD brains. Even in familial AD, oxidative stress plays an important role in the early onset of the disease. Mitochondrial damage and proteasome inhibition represent early events in the pathogenesis of AD, whereas increased processing of amyloid precursor protein (APP) to beta-amyloid (Abeta) fragments (Abeta(40) and Abeta(42)) and formation of senile plaques and neurofibrillary tangles (NFTs) represent late events. We propose a hypothesis that in idiopathic AD, epigenetic components of neurons such as mitochondria, proteasomes and post-translation protein modifications (processing of amyloid precursor protein to beta-amyloid and hyperphosphorylation of tau), rather than nuclear genes, are the primary targets for the action of diverse groups of neurotoxins. Based on epidemiologic, laboratory and limited clinical studies, we propose that a combination of non steroidal anti-inflammatory drugs (NSAIDs) and appropriate levels and types of multiple micronutrients, including antioxidants, may be more effective than the individual agents in the prevention, and they, in combination with a cholinergic agent, may be more effective in the treatment of AD than the individual agents alone. In addition, agents, which can prevent formation of plaques or dissolve these plaques may further enhance the efficacy of our proposed treatment strategy.
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PMID:Risk factors for Alzheimer's disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment. 1248 Jul 96

Beta-amyloid peptide (Abeta) plays a central role in mediating neurotoxicity and in the formation of senile plaques in Alzheimer's disease (AD). The investigation of the roles of ubiquitin (Ub) in the process underlying the association of abnormal protein with the inclusion bodies that characterize AD is of great importance for the further understanding of this disorder. We have used primary cultures of cortical neurons and astrocytes to investigate the participation of the Ub-proteasome pathway in the degradation of Abeta and the effect of Abeta(1-42) and of the fragment Abeta(25-35) upon neural cells. We have found that Abeta(25-35) and Abeta(1-42) produce a significant increase in Ub-protein conjugates and in the expression of the Ub-activating enzyme E1. On the other hand, beta peptides inhibited the proteolytic activities of the 26S proteasome. When the proteolytic activity of the 26S proteasome was inhibited with lactacystin, there was a marked decrease in Abeta(1-42) degradation, suggesting that the peptide, in both astrocytes and neurons, could be a possible substrate of this enzymatic complex. Treatment of the cultures with lactacystin prior to the exposure to Abeta produced a significant decrease in cell viability, possibly as a consequence of the inhibition of Abeta degradation leading to a persistent exposure of the cells to the amyloidogenic peptide which results in cell death. Alterations in the Ub-proteasome pathway in AD could affect the normal proteolytic removal of Abeta, leading to an abnormal accumulation of Abeta(1-42).
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PMID:Relationship between beta-amyloid degradation and the 26S proteasome in neural cells. 1268 27


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