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)

Mitochondrial abnormalities represent a major cytopathology in Huntington's disease (HD), a fatal neurodegenerative disease caused by CAG repeat expansions in the gene encoding huntingtin (Htt). In the present study, we investigated whether defects in the mitochondrial respiratory function are consequences of the expression of mutant Htt or they promote the formation of Htt aggregates. To take advantage of existing mitochondrial DNA mutants, we developed human osteosarcoma 143B cells expressing mutant Htt in an inducible manner and found that cells expressing mutant Htt but not wild-type Htt exhibited a reduced activity of complex III and an increased activity of complex IV. Conversely, pharmacological treatments that inhibited complex III activity significantly promoted the formation of Htt aggregates. This complex III-mediated modulation of Htt aggregates was also observed in a neuronal progenitor RN33B cell line transduced by lentivirus carrying mutant Htt. This effect of complex III inhibition on the Htt aggregates appeared to be mediated by the inhibition of proteasome activity, but not by ATP depletion or production of reactive oxygen species. Accordingly, complex III mutant cells also showed decreased proteasome activity. These results suggest the presence of a feedback system connecting the mitochondrial respiratory complex III and the production of Htt aggregates. Our results suggest that therapeutic interventions targeting complex III and/or proteasome could ameliorate the progress of HD.
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PMID:Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates. 1735 14

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disease caused by an abnormally expanded CAG repeat in the HD gene. Ubiquitylated aggregates containing mutant huntingtin protein in neurons are hallmarks of HD. Misfolded mutant huntingtin monomers, oligomers, or aggregates may be a result of, and cause, ubiquitin- proteasome dysfunction. To investigate the ubiquitin-proteasome system we designed a series of firefly luciferase reporters targeted selectively to different points along this pathway. These reporters were used to monitor ubiquitin-proteasome system function in a striatal cell culture model of HD. Ubiquitylation processes were not reduced in mutant huntingtin cells but recognition or degradation of ubiquitylated substrates was decreased. We also found mutant huntingtin expressing cells had slight but significant decreases in chymotrypsin-like and caspase-like activities, and an unexpected increase in trypsin-like activity of the proteasome core. General proteasome core inhibitors, as well as selective caspase-like activity inhibitors, were less effective in mutant cells. Finally, treatment with 3-nitropropionic acid, a succinate dehydrogenase inhibitor, had opposite effects on the ubiquitin-proteasome system with activation in wild-type and decreased activity in mutant huntingtin expressing cells. The results of these experiments show clearly selective disruption of the ubiquitin-proteasome system in this cell culture model of HD. The high throughput tools that we have designed and optimized will also be useful in identifying compounds that alter ubiquitin-proteasome system function and to investigate other neurodegenerative diseases such Alzheimer's disease and Parkinson's disease.
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PMID:Ubiquitin-proteasome system alterations in a striatal cell model of Huntington's disease. 1745 94

Sumoylation is a post-translational modification by which small ubiquitin-like modifiers (SUMO) are covalently conjugated to target proteins. This reversible pathway provides a rapid and efficient way to modulate the subcellular localization, activity and stability of a wide variety of substrates. Similar to its well-known cousin ubiquitin, SUMO co-localize with the neuronal inclusions associated with several neurodegenerative diseases, including multiple system atrophy, Huntington's disease and other related polyglutamine disorders. The identification of huntingtin, ataxin-1, tau and alpha-synuclein as SUMO substrates further supports the involvement of sumoylation in the pathogenesis of this family of neurological diseases. In addition to direct targeting of these constituent proteins, sumoylation also impacts other disease pathways such as oxidative stress, protein aggregation and proteasome-mediated degradation. This review highlights the recent advances in understanding the contributions of SUMO to neurodegeneration and the underlying pathogenic mechanisms of these diseases.
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PMID:SUMO on the road to neurodegeneration. 1747 50

Ubiquitylated inclusion bodies (IBs) found in Huntington's disease (HD) postulate an impaired ubiquitin-proteasome system. However, this hypothesis remains controversial. In vitro-generated polyglutamine aggregates failed to inhibit purified proteasomes, while filamentous huntingtin aggregates isolated from mice resulted in inhibition. However, similarly isolated IBs did not, thus suggesting that IB formation is protective by sequestering smaller inhibitory aggregates. Accordingly, proteasome-activity assays in IB-containing mouse brain homogenates did not show decreased activity. On the contrary, some of the endoproteolytic proteasome activities increased, probably due to altered subunit composition. However, activity was found decreased in postmortem human HD tissue. Finally, evidence supporting the hypothesis was found in HD cell models expressing fluorescent ubiquitin-proteasome system reporters but not in retina of SCA-7 mice with similar reporters. In summary, it seems that mutant huntingtin, probably in intermediate aggregate forms, has the potential to inhibit proteasome activity, but the global status of the system in HD brain tissue is not yet fully elucidated.
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PMID:Is the ubiquitin-proteasome system impaired in Huntington's disease? 1760 96

The effect of normal cellular prion protein (PrP(C)) on abnormal protein aggregation was examined by transfecting huntingtin fragments (Htt) into SN56 neuronal-derived cells depleted of PrP(C) by RNA interference. PrP(C) depletion caused an increase in both the number of cells containing granules and the number of apoptotic cells. Consistent with the increase in Htt aggregation, PrP(C) depletion caused an decrease in proteasome activity and a decrease in the activities of cellular defense enzymes compared with control cells whereas reactive oxygen species (ROS) increased more than threefold. Therefore, PrP(C) may protect against Htt toxicity in neuronal cells by increasing cellular defense proteins, decreasing ROS and increasing proteasome activity thereby increasing Htt degradation. Depletion of endogenous PrP(C) in non-neuronal Caco-2 and HT-29 cells did not affect ROS levels or proteasome activity suggesting that only in neuronal cells does PrP(C) confer protection against Htt toxicity. The protective effect of PrP(C) was further evident in that overexpression of mouse PrP(C) in SN56 cells transfected with Htt caused a decrease in both the number of cells with Htt granules and the number of apoptotic cells, whereas there was no effect of PrP(C) expression in non-neuronal NIH3T3 or CHO cells. Finally, in chronically scrapie (PrP(Sc))-infected cells, ROS increased more than twofold while proteasome activity was decreased compared to control cells. Although this could be a direct effect of PrP(Sc), it is also possible that, since PrP(C) specifically prevents pathological protein aggregation in neuronal cells, partial loss of PrP(C) itself increases PrP(Sc) aggregation.
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PMID:Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation. 1763 96

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expansion of CAG triplet repeats in the huntingtin (HTT) gene (also called HD) and characterized by accumulation of aggregated fragments of polyglutamine-expanded HTT protein in affected neurons. Abnormal enrichment of HD inclusion bodies with ubiquitin, a diagnostic characteristic of HD and many other neurodegenerative disorders including Alzheimer's and Parkinson's diseases, has suggested that dysfunction in ubiquitin metabolism may contribute to the pathogenesis of these diseases. Because modification of proteins with polyubiquitin chains regulates many essential cellular processes including protein degradation, cell cycle, transcription, DNA repair and membrane trafficking, disrupted ubiquitin signalling is likely to have broad consequences for neuronal function and survival. Although ubiquitin-dependent protein degradation is impaired in cell-culture models of HD and of other neurodegenerative diseases, it has not been possible to evaluate the function of the ubiquitin-proteasome system (UPS) in HD patients or in animal models of the disease, and a functional role for UPS impairment in neurodegenerative disease pathogenesis remains controversial. Here we exploit a mass-spectrometry-based method to quantify polyubiquitin chains and demonstrate that the abundance of these chains is a faithful endogenous biomarker of UPS function. Lys 48-linked polyubiquitin chains accumulate early in pathogenesis in brains from the R6/2 transgenic mouse model of HD, from a knock-in model of HD and from human HD patients, establishing that UPS dysfunction is a consistent feature of HD pathology. Lys 63- and Lys 11-linked polyubiquitin chains, which are not typically associated with proteasomal targeting, also accumulate in the R6/2 mouse brain. Thus, HD is linked to global changes in the ubiquitin system to a much greater extent than previously recognized.
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PMID:Global changes to the ubiquitin system in Huntington's disease. 1768 26

Skp1, Cul1, Rbx1, and the FBXO25 protein form a functional ubiquitin ligase complex. Here, we investigate the cellular distribution of FBXO25 and its colocalization with some nuclear proteins by using immunochemical and biochemical approaches. FBXO25 was monitored with affinity-purified antibodies raised against the recombinant fragment spanning residues 2-62 of the FBXO25 sequence. FBXO25 protein was expressed in all mouse tissues tested except striated muscle, as indicated by immunoblot analysis. Confocal analysis revealed that the endogenous FBXO25 was partially concentrated in a novel dot-like nuclear domain that is distinct from clastosomes and other well-characterized structures. These nuclear compartments contain a high concentration of ubiquitin conjugates and at least two other components of the ubiquitin-proteasome system: 20S proteasome and Skp1. We propose to name these compartments FBXO25-associated nuclear domains. Interestingly, inhibition of transcription by actinomycin D or heat-shock treatment drastically affected the nuclear organization of FBXO25-containing structures, indicating that they are dynamic compartments influenced by the transcriptional activity of the cell. Also, we present evidences that an FBXO25-dependent ubiquitin ligase activity prevents aggregation of recombinant polyglutamine-containing huntingtin protein in the nucleus of human embryonic kidney 293 cells, suggesting that this protein can be a target for the nuclear FBXO25 mediated ubiquitination.
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PMID:FBXO25-associated nuclear domains: a novel subnuclear structure. 1828 34

Huntington's disease (HD) is caused by the expansion of a polyglutamine tract in the N-terminal region of huntingtin (htt) and is characterized by selective neurodegeneration. In addition to forming nuclear aggregates, mutant htt accumulates in neuronal processes as well as synapses and affects synaptic function. However, the mechanism for the synaptic toxicity of mutant htt remains to be investigated. We targeted fluorescent reporters for the ubiquitin-proteasome system (UPS) to presynaptic or postsynaptic terminals of neurons. Using these reporters and biochemical assays of isolated synaptosomes, we found that mutant htt decreases synaptic UPS activity in cultured neurons and in HD mouse brains that express N-terminal or full-length mutant htt. Given that the UPS is a key regulator of synaptic plasticity and function, our findings offer insight into the selective neuronal dysfunction seen in HD and also establish a method to measure synaptic UPS activity in other neurological disease models.
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PMID:Impaired ubiquitin-proteasome system activity in the synapses of Huntington's disease mice. 1836 79

The ubiquitin-proteasome and autophagy-lysosomal pathways are the two main routes of protein and organelle clearance in eukaryotic cells. The proteasome system is responsible for unfolded, short-lived proteins, which precludes the clearance of oligomeric and aggregated proteins, whereas macroautophagy, a process generally referred to as autophagy, mediates mainly the bulk degradation of long-lived cytoplasmic proteins, large protein complexes or organelles.(1) Recently, the autophagy-lysosomal pathway has been implicated in neurodegenerative disorders as an important pathway for the clearance of abnormally accumulated intracellular proteins, such as huntingtin, tau and mutant and modified alpha-synuclein.(1-6) Our recent study illustrated the induction of adaptive autophagy in response to mutant glial fibrillary acidic protein (GFAP) accumulation in astrocytes, in the brains of patients with Alexander disease (AxD), and in mutant GFAP knock-in mouse brains.(7) This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). The activation of p38 MAPK by GFAP accumulation is responsible for mTOR inactivation and the induction of autophagy. We also found that the accumulation of GFAP impairs proteasome activity.(8) In this commentary we discuss the potential compensatory relationship between an impaired proteasome and activated autophagy, and propose that the MLK-MAPK (mixed lineage kinase-mitogen-activated protein kinase) cascade is a regulator of this crosstalk.
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PMID:Adaptive autophagy in Alexander disease-affected astrocytes. 1841 43

Huntington's disease is caused by polyglutamine expansion in the huntingtin protein. Huntingtin directly interacts with profilin, a major actin monomer sequestering protein and a key integrator of signals leading to actin polymerization. We observed a progressive loss of profilin in the cerebral cortex of Huntington's disease patients, and in cell culture and Drosophila models of polyglutamine disease. This loss of profilin is likely due to increased degradation through the ubiquitin proteasome system. Profilin loss reduces the F/G actin ratio, indicating a shift in actin polymerization. Overexpression of profilin abolishes mutant huntingtin toxicity in cells and partially ameliorates the morphological and functional eye phenotype and extends lifespan in a transgenic polyglutamine Drosophila model. These results indicate a link between huntingtin and profilin and implicate profilin in Huntington's disease pathogenesis.
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PMID:Expression of expanded polyglutamine targets profilin for degradation and alters actin dynamics. 1841 52


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