Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TNF plays a pivotal role in the pathogenesis of a broad spectrum of infectious, inflammatory, and autoimmune diseases. In addition to the secreted, mature 17 kD form, TNF exists as a bioactive precursor 26 kD transmembrane protein. Transmembrane TNF signaling has been directly associated with specific immune mechanisms, including the contact-dependent lymphocyte and monocyte-mediated cell killing and the CD40 ligand-independent, T cell-mediated polyclonal B cell activation. In previous studies, we have reported that mice expressing 3'-UTR modified human TNF transgenes develop chronic inflammatory polyarthritis with a 100% phenotypic penetrance and timed disease onset. In additional experiments, we have also shown that high-level expression of human TNF in lymphoid cells of transgenic mice results in both local (thymic hypoplasia) and systemic (ischaemia, tissue necrosis, and wasting) TNF-mediated pathology. In this study we show that transgenic mice expressing a T cell-targeted membrane-associated mutant human TNF alpha protein are displaying only local TNF-mediated pathologies, ranging from lymphoid tissue derangements to proliferative synovitis and chronic inflammatory arthritis. These results demonstrate that in vivo, at least part of the pathogenic activities of TNF alpha may be assigned to the functioning of its uncleaved, membrane-associated form.
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PMID:Transmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. 873 89

Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs). We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death.
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PMID:Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease. 1610 21

Recent studies have identified a novel bone-kidney endocrine axis that maintains phosphate homeostasis. When phosphate is in excess, fibroblast growth factor-23 (FGF23) is secreted from bone and acts on the kidney to promote phosphate excretion into urine and suppress vitamin D synthesis, thereby inducing negative phosphate balance. One critical feature of FGF23 is that it requires Klotho, a single-pass transmembrane protein expressed in renal tubules, as an obligate coreceptor to bind and activate FGF receptors. Several hereditary disorders that exhibit inappropriately high serum FGF23 levels are associated with phosphate wasting and impaired bone mineralization. In contrast, defects in either FGF23 or Klotho are associated with phosphate retention and a premature-aging syndrome. The aging-like phenotypes in Klotho-deficient or FGF23-deficient mice can be rescued by resolving hyperphosphatemia with dietary or genetic manipulation, suggesting a novel concept that phosphate retention accelerates aging. Phosphate retention is universally observed in patients with chronic kidney disease (CKD) and identified as a potent risk of death in epidemiological studies. Thus, the bone-kidney endocrine axis mediated by FGF23 and Klotho has emerged as a novel target of therapeutic interventions in CKD.
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PMID:Overview of the FGF23-Klotho axis. 1962 41

Emery-Dreifuss muscular dystrophy (EDMD) is a progressive muscle-wasting disorder defined by early contractures of the Achilles tendon, spine, and elbows. EDMD is also distinctive for its association with defects of the cardiac conduction system that can result in sudden death. It can be inherited in an X-linked, autosomal dominant, or autosomal recessive fashion and is caused by mutations in proteins of the nuclear membrane. Mutations in the EMD gene, which encodes emerin, a transmembrane protein found at the inner nuclear membrane, are responsible for X-linked EDMD. The most common etiology of autosomal dominant EDMD is an LMNA gene mutation; LMNA encodes the intermediate filament protein lamins A and C, which constitute the major scaffolding protein of the inner nuclear membrane. Murine models of LMNA gene mutations have helped to identify different mechanisms of disease. Loss of LMNA function leads to nuclear fragility as well as other defects, such as abnormal nuclear function. Additional genes encoding nuclear membrane proteins such as SYNE1 and SYNE2 have also been implicated in EDMD, and in some cases their importance for cardiac and muscle function has been supported by animal modeling.
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PMID:Emery-Dreifuss muscular dystrophy. 2149 32

Removal of ubiquitinated targets by autophagosomes can be mediated by receptor molecules, like SQSTM1, in a mechanism referred to as selective autophagy. While cytoplasmic protein aggregates, mitochondria, and bacteria are the best-known targets of selective autophagy, their role in the turnover of membrane receptors is scarce. We here showed that fasting-induced wasting of skeletal muscle involves remodeling of the neuromuscular junction (NMJ) by increasing the turnover of muscle-type CHRN (cholinergic receptor, nicotinic/nicotinic acetylcholine receptor) in a TRIM63-dependent manner. Notably, this process implied enhanced production of endo/lysosomal carriers of CHRN, which also contained the membrane remodeler SH3GLB1, the E3 ubiquitin ligase, TRIM63, and the selective autophagy receptor SQSTM1. Furthermore, these vesicles were surrounded by the autophagic marker MAP1LC3A in an ATG7-dependent fashion, and some of them were also positive for the lysosomal marker, LAMP1. While the amount of vesicles containing endocytosed CHRN strongly augmented in the absence of ATG7 as well as upon denervation as a model for long-term atrophy, denervation-induced increase in autophagic CHRN vesicles was completely blunted in the absence of TRIM63. On a similar note, in trim63(-/-) mice denervation-induced upregulation of SQSTM1 and LC3-II was abolished and endogenous SQSTM1 did not colocalize with CHRN vesicles as it did in the wild type. SQSTM1 and LC3-II coprecipitated with surface-labeled/endocytosed CHRN and SQSTM1 overexpression significantly induced CHRN vesicle formation. Taken together, our data suggested that selective autophagy regulates the basal and atrophy-induced turnover of the pentameric transmembrane protein, CHRN, and that TRIM63, together with SH3GLB1 and SQSTM1 regulate this process.
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PMID:Role of autophagy, SQSTM1, SH3GLB1, and TRIM63 in the turnover of nicotinic acetylcholine receptors. 2422 May 1