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)

Due to its exposed position, the MCP joint of the thumb is particularly vulnerable to dislocations and fracture dislocations. Depending on the direction of the injuring force, injuries to the ulnar, radial, and volar aspect of the joint can occur. If high-grade lesions are not identified and treated appropriately during their acute phase, marked instability with associated long-term disability due to weakness and pain in pinch and grip can result. In the absence of a reliable method for diagnosing the Stener lesion, surgical repair of acute, third-degree lesions on the ulnar side of the joint remains the treatment of choice. In the presence of chronic instability, a variety of effective soft tissue reconstructive measures are available. The fact that both acute and chronic injuries enjoy a favorable prognosis with operative repair is due to the fact that operative intervention reliably restores stability to the joint. Mild to moderate loss of motion at the joint is well tolerated functionally. For this reason, arthrodesis remains an exceptionally satisfactory salvage for failed soft tissue reconstructions.
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PMID:Dislocations and fracture dislocations of the metacarpophalangeal joint of the thumb. 327 79

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. The autosomal dominant form of the disease is caused by short (GCG)(8-13) expansions in the PABP2 gene. This gene encodes the poly(A) binding protein 2 (PABP2), an abundant nuclear protein that binds with high affinity to nascent poly(A) tails, stimulating their extension and controlling their length. In this work we report that PABP2 is detected in filamentous nuclear inclusions, which are the pathological hallmark of OPMD. Using both immunoelectron microscopy and fluorescence confocal microscopy, the OPMD-specific nuclear inclusions appeared decorated by anti-PABP2 antibodies. In addition, the inclusions were labeled with antibodies directed against ubiquitin and the subunits of the proteasome and contained a form of PABP2 that was more resistant to salt extraction than the protein dispersed in the nucleoplasm. This suggests that the polyalanine expansions in PABP2 induce a misfolding and aggregation of the protein into insoluble inclusions, similarly to events in neurodegenerative diseases caused by CAG/polyglutamine expansions. No significant differences were observed in the steady-state poly(A) tail length in OPMD and normal myoblasts. However, the nuclear inclusions were shown to sequester poly(A) RNA. This raises the possibility that in OPMD the polyalanine expansions in the PABP2 protein may interfere with the cellular traffic of poly(A) RNA.
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PMID:Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA. 1100 36

A 22-year-old man developed unconsciousness, severe quadriplegia and muscle atrophy, and had markedly elevated serum creatine kinase levels after using the high-dose steroid and nondepolarizing neuromuscular blocking agents during the course of sepsis and DIC. On neurological examination, he was lethargic. The patient had generalized muscle weakness and wasting, and diminished deep tendon reflexes. He weakly responsed to painful stimuli on the legs. The motor nerve conduction study demonstrated decreased CMAP (compound muscle action potential) amplitudes. Motor and sensory nerve conduction velocities and their distal latencies were normal. Muscle biopsy revealed marked muscle fiber atrophy predominantly in type 2 fibers and numerous basophilic and a few necrotic fibers. Some atrophic fibers had decreased to absent myosin adenosine triphosphatase activity in their center. Accordingly, he was diagnosed as having acute quadriplegic myopathy (AQM), which has been reported mainly in Western countries. The mechanism of muscle fiber degradation in this myopathy is still unknown. On immunohistochemical analysis to our patient, enzyme activities of various proteases such as calpain, cathepsin B, and proteasomes were increased in the sarcoplasm, especially in the atrophic fibers. We suggest that lysosomal cathepsin, nonlysosomal calpain, and ATP-ubiquitin-proteasome proteolytic pathways participate in muscle fiber degradation in AQM.
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PMID:[A case of acute quadriplegic myopathy]. 1108 98

Muscle catabolism is an important component of the metabolic response to stress and injury, including sepsis and burn injury. Muscle wasting and weakness in catabolic patients may adversely affect the outcome in these patients owing to delayed ambulation and involvement of respiratory muscles. An understanding of the regulation of muscle protein breakdown during sepsis and following injury therefore is of great importance from a clinical standpoint and is essential for the development of new therapeutic modalities to prevent protein loss from muscle tissue. Studies in experimental animals and in patients have provided evidence that the myofibrillar proteins actin and myosin are particularly sensitive to the effects of sepsis and injury. (Glucocorticoids, interleukin-1, and tumor necrosis factor participate in the regulation of muscle protein breakdown. Most muscle proteins are degraded by the ubiquitin-proteasome-dependent proteolytic pathway. Because the proteasome does not degrade intact myofibrils, a calcium-dependent Z-band disintegration and release of myofilaments from the myofibrils may be an important initial step of muscle breakdown during sepsis and other catabolic conditions. Continued studies to define mechanisms of the catabolic response to stress and injury are important for improving the metabolic care of patients with muscle catabolism.
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PMID:Catabolic response to stress and injury: implications for regulation. 1119 8

Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide cytokine that has been associated with muscle wasting and weakness in inflammatory disease. Despite its potential importance in muscle pathology, the direct effects of TNF-alpha on skeletal muscle have remained undefined until recently. Studies of cultured muscle cells indicate that TNF-alpha disrupts the differentiation process and can promote catabolism in mature cells. The latter response appears to be mediated by reactive oxygen species and nuclear factor-kappaB which upregulate ubiquitin/proteasome activity. This commentary outlines our current understanding of TNF-alpha effects on skeletal muscle and the mechanism of TNF-alpha action.
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PMID:Tumor necrosis factor-alpha and muscle wasting: a cellular perspective. 1168 94

The molecular events by which eccentric muscle contractions induce muscle damage and remodelling remain largely unknown. We assessed whether eccentric exercise modulates the expression of proteinases (calpains 1, 2 and 3, proteasome, cathepsin B+L), muscle structural proteins (alpha-sarcoglycan and desmin), and the expression of the heat shock proteins Hsp27 and alphaB-crystallin. Vastus lateralis muscle biopsies from twelve healthy male volunteers were obtained before, immediately after, and 1 and 14 days after a 30 min downhill treadmill running exercise. Eccentric exercise induced muscle damage as evidenced by the analysis of muscle pain and weakness, creatine kinase serum activity, myoglobinaemia and ultrastructural analysis of muscle biopsies. The calpain 3 mRNA level was decreased immediately after exercise whereas calpain 2 mRNA level was increased at day 1. Both mRNA levels returned to control values by day 14. By contrast, cathepsin B+L and proteasome enzyme activities were increased at day 14. The alpha-sarcoglycan protein level was decreased immediately after exercise and at day 1, whereas the desmin level peaked at day 14. alphaB-crystallin and Hsp27 protein levels were increased at days 1 and 14. Our results suggest that the differential expression of calpain 2 and 3 mRNA levels may be important in the process of exercise-induced muscle damage, whereas expression of alpha-sarcoglycan, desmin, alphaB-crystallin and Hsp27 may be essentially involved in the subsequent remodelling of myofibrillar structure. This remodelling response may limit the extent of muscle damage upon a subsequent mechanical stress.
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PMID:Molecular adaptations of neuromuscular disease-associated proteins in response to eccentric exercise in human skeletal muscle. 1218

Muscular inactivity leads to atrophy, weakness, and decreased fatigue resistance. In order to provide a window into the dynamic processes that underlie muscle atrophy, we performed global gene expression analysis of rat soleus muscles using Affymetrix GeneChips at 1, 4, 7 and 14 days of hindlimb unloading. Expression of 309 known genes was significantly changed by at least 2-fold (212 upregulated, 97 downregulated). K-means clustering was used to divide these genes into co-regulated clusters based on the similarity of temporal expression patterns. This allowed the development of a timeline of the atrophy process with respect to the behaviour of genes in a broad array of functional categories. Regulatory genes were often upregulated early, in either a transient or sustained manner, but they also populated clusters with later patterns of activation, suggesting different phases of molecular adaptations. Other early events were the activation of ubiquitination genes and downregulation of protein chaperones. In comparison, clusters representing slightly delayed activation patterns included genes involved in fast contraction, glycolysis, translational inhibition, oxidative stress, protein degradation, and amino acid catabolism. Downregulated genes exhibited fewer unique expression patterns and included structural and regulatory genes of the extracellular matrix and cytoskeleton, and genes that define a slow-oxidative phenotype. Other novel findings include the tight co-activation of proteasome subunit and ubiquitination genes, differential regulation of serine proteases and serine protease inhibitors, and the identification of transcriptional, signalling, growth and cell cycle genes that probably play a role in the atrophy process. The present work has uncovered temporal patterns of gene expression that highlight the molecular processes that underlie muscle atrophy and provide new avenues for study.
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PMID:Global analysis of gene expression patterns during disuse atrophy in rat skeletal muscle. 1284 9

Cachexia is a syndrome and therefore does not have a specific definition. Patients are characterized by the presence of anorexia, early satiety, weight loss, weakness, anaemia and oedema. These features occur to a variable extent in different patients and may change in severity during the course of a patient's illness. The multifactorial origin of cachexia precludes a uniform pathophysiological definition. Taken together these factors have hindered clinical studies both at a fundamental level and in terms of the introduction of effective therapy. The advent of novel therapeutic targets (e.g., ubiquitin-proteasome pathway) and biological response modifiers has opened possibilities for new clinical trials in cachexia. Regulatory authorities feel it is important not only to demonstrate efficacy in terms of patients' nutritional status (e.g., lean body mass) but also functional status (e.g., performance status). This article reviews current methods to assess the latter. Methods focused on measuring physical activity level (e.g., doubly labelled water technique or physical activity meters) promise objective data which can be readily interpreted in terms of clinically meaningful benefit.
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PMID:Research methodology: cancer cachexia syndrome. 1533 19

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies characterized by progressive weakness and atrophy of distal limb muscles. Recently, SIMPLE/LITAF was shown to be responsible for an autosomal dominant demyelinating form of CMT linked to 16p (CMT1C). Although two transcripts encoding different proteins (SIMPLE and LITAF) have been reported from the same gene, we could not confirm the existence of LITAF. Here we show that the LITAF transcript appears to result from a DNA sequencing error. We screened the SIMPLE gene for mutations in a cohort of 192 patients with CMT or related neuropathies, each of whom tested negative for other known genetic causes of CMT. In 16 unrelated CMT families we identified nine different nucleotide variations in SIMPLE that were not detected in control chromosomes. SIMPLE mutations can occur de novo, associated with sporadic CMT1 and may convey both demyelinating and axonal forms. Bioinformatics analyses and other observations of SIMPLE suggest that 1) it could be a member of the RING finger motif-containing subfamily of E3 ubiquitin ligases that are associated with the ubiquitin-mediated proteasome processing pathway, 2) it could interact through its PPXY motifs with a WW domain containing protein, for instance with NEDD4, an E3 ubiquitin ligase, and 3) it could interact through the PSAP motif with TSG10, a protein associated with endosomal multivesicular protein sorting. Since both SIMPLE and Hrs are endosomal proteins and have both PPXY and P(S/T)AP motifs, we hypothesize that SIMPLE, like Hrs, is potentially a clathrin adaptor aiding in the retention of ubiquitinated proteins on to the endosomes. Thus the potential E3 ubiquitin ligase activity of SIMPLE, alteration in its interactions with NEDD4 or TSG101, or changes in its properties as a clathrin coat adaptor may underlie the pathogenesis of Charcot-Marie-Tooth disease.
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PMID:SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. 1577 29

One of the most important effects of aging is sarcopenia, which is associated with impaired locomotion and general weakness. In addition, there is increased susceptibility to illness in aging, which often results in muscle wasting episodes. In such instances, the mobilization of muscle proteins provides free amino acids that are used for energetic purpose, the synthesis of acute phase proteins, and the immune response. However, since muscle protein mass is already depleted, the ability of the aged organism to recover from stress is impaired. Therefore, elucidating the mechanisms that result in sarcopenia is of obvious importance. Age-related changes in protein synthesis and proteolysis are rather small and our current methodology does not enable one to establish unequivocally whether sarcopenia results from depressed protein synthesis, increased proteolysis or both. By contrast, in anabolic and catabolic periods, a number of dysregulations in muscle protein turnover became clearly apparent. The aim of this review is to provide an overview of such altered responses to nutrients and catabolic treatments, which may ultimately contribute to explain sarcopenia. This includes impaired recovery in catabolic states, impaired anabolic effects of nutrients, in particular leucine, and a lack of regulation of the ubiquitin-proteasome proteolytic system. These alterations are discussed with respect to modifications in the insulin/IGF-1 axis and glucocorticoid related effects.
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PMID:Altered responses in skeletal muscle protein turnover during aging in anabolic and catabolic periods. 1590 14


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