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)

A unifying feature of many neurodegenerative disorders is the accumulation of polyubiquitinated protein inclusions in dystrophic neurons, e.g. containing alpha-synuclein, which is suggestive of an insufficient proteasomal activity. We demonstrate that alpha-synuclein and 20 S proteasome components co-localize in Lewy bodies and show that subunits from 20 S proteasome particles, in contrast to subunits of the 19 S regulatory complex, bind efficiently to aggregated filamentous but not monomeric alpha-synuclein. Proteasome binding to insoluble alpha-synuclein filaments and soluble alpha-synuclein oligomers results in marked inhibition of its chymotrypsin-like hydrolytic activity through a non-competitive mechanism that is mimicked by model amyloid-Abeta peptide aggregates. Endogenous ligands of aggregated alpha-synuclein like heat shock protein 70 and glyceraldehyde-6-phosphate dehydrogenase bind filaments and inhibit their anti-proteasomal activity. The inhibitory effect of amyloid aggregates may thus be amenable to modulation by endogenous chaperones and possibly accessible for therapeutic intervention.
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PMID:Proteasomal inhibition by alpha-synuclein filaments and oligomers. 1471 27

Polyglutamine expansion in the N terminus of huntingtin (htt) causes selective neuronal dysfunction and cell death by unknown mechanisms. Truncated htt expressed in vitro produced htt immunoreactive cytoplasmic bodies (htt bodies). The fibrillar core of the mutant htt body resisted protease treatment and contained cathepsin D, ubiquitin, and heat shock protein (HSP) 40. The shell of the htt body was composed of globules 14-34 nm in diameter and was protease sensitive. HSP70, proteasome, dynamin, and the htt binding partners htt interacting protein 1 (HIP1), SH3-containing Grb2-like protein (SH3GL3), and 14.7K-interacting protein were reduced in their normal location and redistributed to the shell. Removal of a series of prolines adjacent to the polyglutamine region in htt blocked formation of the shell of the htt body and redistribution of dynamin, HIP1, SH3GL3, and proteasome to it. Internalization of transferrin was impaired in cells that formed htt bodies. In cortical neurons of Huntington's disease patients with early stage pathology, dynamin immunoreactivity accumulated in cytoplasmic bodies. Results suggest that accumulation of a nonfibrillar form of mutant htt in the cytoplasm contributes to neuronal dysfunction by sequestering proteins involved in vesicle trafficking.
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PMID:Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. 1471 59

Possible target proteins of cytosolic thioredoxin in higher plants have been investigated in the cell lysate of dark-grown Arabidopsis thaliana whole tissues. We immobilized a mutant of cytosolic thioredoxin, in which an internal cysteine at the active site was substituted with serine, on CNBr activated resin, and used the resin for the thioredoxin-affinity chromatography. By using this resin, the target proteins for thioredoxin in the higher plant cytosol were efficiently acquired. The obtained proteins were separated by two-dimensional gel electrophoresis and analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Thus we have identified proteins of the anti-oxidative stress system proteins (ascorbate peroxidase, germin-like protein, and monomeric type II peroxiredoxin), proteins involved in protein biosynthesis (elongation factor-2 and eukaryotic translation initiation factor 4A), proteins involved in protein degradation (the regulatory subunit of 26S proteasome), and several metabolic enzymes (alcohol dehydrogenase, fructose 1,6-bis phosphate aldolase-like protein, cytosolic glyceraldehyde 3-phosphate dehydrogenase, cytosolic malate dehydrogenase, and vitamin B(12)-independent methionine synthase) together with some chloroplast proteins (chaperonin 60-alpha and 60-beta, heat shock protein 70, and glutamine synthase). The results in this study and recent proteomics studies on the target proteins of chloroplast thioredoxin indicate the versatility and the physiological significance of thioredoxin as reductant in plant cell.
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PMID:Target proteins of the cytosolic thioredoxins in Arabidopsis thaliana. 1474 82

BAG-1 (Bcl-2-associated athanogene-1) proteins interact with the HSC70 and HSP70 heat shock proteins and have been proposed to promote cell survival by coordinating the function of these chaperones with the proteasome to facilitate protein degradation. Consistent with this proposal, previous analyses in cancer cells have demonstrated that BAG-1 requires protein domains important for HSC70/HSP70 and proteasome binding in order to interfere with the growth inhibition induced by heat shock (Townsend, P. A., Cutress, R. I., Sharp, A., Brimmell, M., and Packham, G. (2003) Cancer Res., 63, 4150-4157). Moreover, cellular stress triggered the relocalization of the cytoplasmic BAG-1S (approximately 36 kDa) isoform to the nucleus, and both BAG-1S and the constitutively nuclear localized BAG-1L (approximately 50 kDa) isoform suppressed heat shock-induced apoptosis to the same extent, suggesting a critical role in the nucleus. Because ischemia (I) and reperfusion (R) are important stress signals in acute and chronic heart disease, we have examined the expression and function of BAG-1 proteins in primary cardiac myocytes (CMs) and the Langendorff-perfused intact heart. The expression of both BAG-1 isoforms, BAG-1S and BAG-1L, was rapidly induced following ischemia in rat CM, and this was maintained during subsequent reperfusion. In control hearts, BAG-1S and BAG-1L were readily detectable in both the nucleus and the cytoplasm. However, BAG-1S did not relocate to the nucleus following simulated I/R. BAG-1 interacted with both RAF-1 and HSC70 in CMs and the whole heart, and binding to HSC70 was increased following I/R. Overexpression of the human BAG-1S and BAG-1 M isoforms significantly reduced CM apoptosis following simulated I/R. By contrast, BAG-1L or BAG-1S fused to a heterologous nuclear localization sequence failed to protect CM. Finally, overexpression of BAG-1 deletion and point mutants unable to bind HSC70/HSP70 failed to offer cardioprotection. Surprisingly, a deletion mutant lacking the N-terminal ubiquitin-like domain, which mediates interaction with the proteasome, still promoted cardioprotection. Therefore, BAG-1 has a novel cardioprotective role, mediated via association with HSC70/HSP70, which is critical upon cytoplasmic localization but independent of the BAG-1 ubiquitin-like domain. Our studies demonstrate that BAG-1 can influence cellular response to stress by multiple mechanisms, potentially influenced by the cell type and nature of the stress signal.
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PMID:BAG-1 proteins protect cardiac myocytes from simulated ischemia/reperfusion-induced apoptosis via an alternate mechanism of cell survival independent of the proteasome. 1497 28

UBB+1 protein is an aberrant ubiquitin associated with progressive supranuclear palsy (PSP). It leads to proteasome inhibition, heat-shock protein (HSP) expression and apoptosis in cell cultures. Despite UBB+1 polyubiquitination (an indication of proteasome inhibition), we demonstrate that UBB+1 and HSP40/HSP70 immunoreactivity do not co-localize in the pons of patients with PSP. As HSPs are involved in both normal tau and proteasome function, these findings may be relevant to the aetiology of PSP and other tauopathies.
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PMID:Failure in heat-shock protein expression in response to UBB+1 protein in progressive supranuclear palsy in humans. 1505 Jul 20

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a hereditary motor neuron disease that affects males, caused by the expansion of a polyglutamine (polyQ) tract in androgen receptor (AR). Female carriers are usually asymptomatic. The transgenic mouse (Tg) model carrying a full-length human AR with expanded polyQ has significant gender-related motor impairment. This phenotype is inhibited by castration, which prevents nuclear translocation of mutant AR. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, also rescues motor dysfunction and nuclear accumulation of mutant AR in the male Tg. Over-expression of a molecular chaperone HSP70, which renatures misfolded mutant AR, ameliorates neuromuscular phenotypes of the Tg by reducing nuclear-localized mutant AR. HSP70 appears to enhance the degradation of mutant AR via ubiquitin-proteasome pathway. These experimental approaches indicate the possibility of clinical application of drugs, such as leuprorelin, for SBMA patients.
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PMID:[Development of therapeutics for spinal and bulbar muscular atrophy (SBMA)]. 1515 1

Aggresomes are associated with many neurodegenerative disorders, including Parkinson's disease, and polyglutamine disorders such as Huntington's disease. These inclusions commonly contain ubiquitylated proteins. The stage at which these proteins are ubiquitylated remains unclear. A malfunction of the ubiquitin/proteasome system (UPS) may be associated with their formation. Conversely, it may reflect an unsuccessful attempt by the cell to remove them. Previously, we demonstrated that overexpression of Parkin, a ubiquitin-protein ligase associated with autosomal recessive juvenile Parkinsonism, generates aggresome-like inclusions in UPS compromised cells. Mutations in the de-ubiquitylating enzyme, UCH-L1, cause a rare form of Parkinsonism. We now demonstrate that overexpression of UCH-L1 also forms ribbon-like aggresomes in response to proteasomal inhibition. Disease-associated mutations, which affect enzymatic activities, significantly increased the number of inclusions. UCH-L1 aggresomes co-localized with ubiquitylated proteins, HSP70, gamma-tubulin and, to a lesser extent, the 20S proteasome and the chaperone BiP. Similar to Parkin inclusions, we found UCH-L1 aggresomes to be surrounded by a tubulin rather than a vimentin cage-like structure. Furthermore, UCH-L1 aggregates with Parkin and alpha-synuclein in some, but not all inclusions, suggesting the heterogeneous nature of these inclusion bodies. This study provides additional evidence that aggregation-prone proteins are likely to recruit UPS components in an attempt to clear proteins from failing proteasomes. Furthermore, UCH-L1 accumulation is likely to play a pathological role in inclusion formation in Parkinson's disease.
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PMID:UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease. 1522 95

Alpha-synuclein (alpha-syn) is a 140-amino acid presinaptic protein whose mutations A30P and A53T have been linked to familiar Parkinson's disease (PD). Many data suggest that alpha-syn aggregation is the key event that triggers alpha-syn-mediated neurotoxicity. Nevertheless, other lines of evidence proposed a protective role of alpha-syn against oxidative stress (a major feature of PD), even if the exact mechanism of this protective action and the role of the pathogenetic mutations to this respect have not been elucidated yet. To address these points, we developed an in vitro model of oxidative stress by exposing PC12 cells to hydrogen peroxide (H2O2) (150 microM) for 72 h, and we evaluated alpha-syn-mediated protection delivering increasing amounts of alpha-syn (wild type [WT] or mutated) inside cells using the fusion proteins TAT-alpha-syn (WT, A30P, and A53T). We found that nanomolar amounts of TAT-alpha-syn-mediated protected against oxidative stress and other cellular injuries (6-hydroxydopamine and serum deprivation), whereas micromolar amounts of the fusion proteins were intrinsically toxic to cells. The protective effect was independent from the presence of the mutations A30P and A53T, but no protection occurred when cells were challenged with the proteasome inhibitors lactacystin and MG132. We verified that the protection mechanism required the presence of the C-terminal domain of alpha-syn, as nanomolar amounts of the C-terminal truncated fusion protein TAT-alpha-syn (WT[1-97]) failed in preventing H2O2 toxicity. To further characterize the molecular mechanisms at the basis of alpha-syn protection, we investigated the possible involvement of the chaperone protein HSP70 that is widely implicated in neuroprotection. We found that, at nanomolar concentrations, TAT-alpha-syn was able to increase HSP70 protein level, whereas at the micromolar scale, TAT-alpha-syn decreased HSP70 at the protein level. These effects on HSP70 were independent from the presence of alpha-syn pathogenetic mutations but required the alpha-syn C-terminal domain. The implications for alpha-syn-mediated neurotoxicity and for PD pathogenesis and progression are discussed.
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PMID:Protective effect of TAT-delivered alpha-synuclein: relevance of the C-terminal domain and involvement of HSP70. 1534 91

Nine neurodegenerative diseases, including spinocerebellar ataxia type 7 (SCA7), are caused by the expansion of polyglutamine stretches in the respective disease-causing proteins. A hallmark of these diseases is the aggregation of expanded polyglutamine-containing proteins in nuclear inclusions that also accumulate molecular chaperones and components of the ubiquitin-proteasome system. Manipulation of HSP70 and HSP40 chaperone levels has been shown to suppress aggregates in cellular models, prevent neuronal death in Drosophila, and improve to some extent neurological symptoms in mouse models. An important issue in mammals is the relative expression levels of toxic and putative rescuing proteins. Furthermore, overexpression of both HSP70 and its co-factor HSP40/HDJ2 has never been investigated in mice. We decided to address this question in a SCA7 transgenic mouse model that progressively develops retinopathy, similar to SCA7 patients. To co-express HSP70 and HDJ2 with the polyglutamine protein, in the same cell type, at comparable levels and with the same time course, we generated transgenic mice that express the heat shock proteins specifically in rod photoreceptors. While co-expression of HSP70 with its co-factor HDJ2 efficiently suppressed mutant ataxin-7 aggregation in transfected cells, they did not prevent either neuronal toxicity or aggregate formation in SCA7 mice. Furthermore, nuclear inclusions in SCA7 mice were composed of a cleaved mutant ataxin-7 fragment, whereas they contained the full-length protein in transfected cells. We propose that differences in the aggregation process might account for the different effects of chaperone overexpression in cellular and animal models of polyglutamine diseases.
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PMID:Hsp70 and Hsp40 chaperones do not modulate retinal phenotype in SCA7 mice. 1549 10

At least nine neurodegenerative disorders are caused by expansion of polyglutamine repeats in various genes. This expansion induces the formation of nuclear inclusions (NI) within various cell types. In this study, we developed a model for polyglutamine diseases using primary cultures of sympathetic neurons from the superior cervical ganglia of prenatal rat pups. Transfection with a plasmid encoding 127 glutamine repeats causes NI to develop in approximately 70% of the sympathetic neurons within 6 days. In addition, it causes somatic atrophy and inhibits dendritic growth. The NIs contain ubiquitinated proteins and sequester the molecular chaperone heat shock protein 70 (Hsp70). We found that two specific proteasome inhibitors, lactacystin and CEP1612, suppress thezformation of polyglutamine-induced NI. In addition, lactacystin treatment induced the removal of preexisting NI. Western blotting and immunocytochemistry revealed that lactacystin and CEP1612 strongly induce the expression of Hsp70, whereas less specific proteasome inhibitor such as N-acetyl-Leu-Leu-Norleucinal does not. Coexpression of 127 glutamines with a plasmid encoding wild-type Hsp70 gene resulted in a marked reduction of the percentage of neurons containing NI. In addition, transfection with plasmids encoding mutant Hsp70 blocked the effects of lactacystin. These findings further implicate Hsp70 as a neuroprotective molecule and they suggest the potential utility of certain proteasome inhibitors in the treatment of polyglutamine diseases.
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PMID:Proteasome inhibitors suppress formation of polyglutamine-induced nuclear inclusions in cultured postmitotic neurons. 1556 48


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