Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin (Ub), a stress protein thought to target abnormal proteins for degradation, is present in abnormal structures that occur in neuronal perikarya and axons of degenerative diseases including Alzheimer disease. To begin to assess the role of the Ub system in the axon, we studied expression and axonal transport of Ub and other stress proteins, as well as of Ub carboxyl-terminal hydrolase PGP 9.5, in the rat visual system in normal conditions and following heat-shock (HS). In the retina, both the constitutive and inducible forms of HSPs 70 were expressed under normal conditions, while in the superior colliculus the inducible form was detected only following HS. Ub, PGP 9.5 and HSPs 70 were transported in the axon exclusively with the slow component b (SCb), known to carry cytoskeletal and cytoplasmic proteins. The exceedingly long time needed for stress proteins to reach distant axonal locales at the rate of SCb (approximately 3 mm/day) makes it unlikely that they could contribute significantly to the stress response at those sites.
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PMID:Axonal transport of two major components of the ubiquitin system: free ubiquitin and ubiquitin carboxyl-terminal hydrolase PGP 9.5. 171 33

Levels of ubiquitin, microtubule associated protein tau and tubulin were determined by immunoassays in homogenates of cerebrum and cerebellum of Alzheimer disease and aged control cases. Ubiquitin levels increased many fold in the cerebral cortex of Alzheimer disease cases and the increase correlated strongly with the degree of neurofibrillary changes in the tissue. The increase in ubiquitin was much less remarkable in the cerebral white matter. Cerebellum which is unaffected with neurofibrillary changes in Alzheimer disease had normal levels of ubiquitin both in gray matter and in white matter. There was an appreciable increase in abnormally phosphorylated tau in an Alzheimer disease brain with severe neurofibrillary degeneration, whereas the normal tau levels were increased only slightly. Tubulin was slightly decreased in the cerebral gray matter but not in the adjacent white matter. Marked increase in brain ubiquitin in Alzheimer disease suggests the role of ubiquitin in the pathobiology of Alzheimer disease.
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PMID:Brain ubiquitin is markedly elevated in Alzheimer disease. 181 31

Several degenerative diseases of the nervous system are characterized by the presence of neuronal inclusions. Most of these inclusions are made of abnormal filaments and share epitopes with cytoskeletal proteins. One of these inclusions, the neurofibrillary tangle of Alzheimer disease, has recently been shown to contain ubiquitin, a regulatory protein thought to play a role in the degradation of abnormal proteins. We carried out light and electron microscopic immunocytochemistry with several polyclonal and monoclonal antibodies to investigate the presence of ubiquitin in neuronal inclusions of neurodegenerative diseases. Ubiquitin was present not only in paired helical filaments that form the neurofibrillary tangle of Alzheimer disease, but also in the filamentous components of the inclusion characteristic of Parkinson disease, Pick disease, and progressive supranuclear palsy. In contrast, ubiquitin was not detected in other neuronal inclusions often found in aging and in Alzheimer disease, such as Hirano bodies and granulovacuolar degeneration. Reactivity with monoclonal antibodies suggests differences in the ubiquitin-acceptor proteins present in the inclusions studied. It is concluded that ubiquitin is selectively present in neuronal inclusions of degenerative diseases.
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PMID:Ubiquitin is associated with abnormal cytoplasmic filaments characteristic of neurodegenerative diseases. 283 68

Neuronal cytoskeleton is composed of microfilaments, neurofilaments and microtubules which show distinctive ultrastructural characteristics. Different groups of antibodies against neurofilaments and microtubule associated proteins which were grouped according to their specificity for proteins of perykarium, axons and/or dendrites have been produced. A 8.6 kD polypeptide called ubiquitin has been recognized as one of the heat shock proteins. Ubiquitin is implicated in the non-lysosomal degradation of abnormal proteins and other proteolytic intracellular mechanisms. Several immunohistological studies on Alzheimer's disease (AD)-neurofibrillary tangles (NFTs) demonstrated that antibodies for different normal cytoskeletal components bind to NFTs-bearing neurons. AD-NFTs could be also demonstrated using antibodies for the beta-amyloid protein. The production and accumulation of abnormal proteins such as those observed in AD-NFTs induce a ubiquitin-mediated degradative pathway to remove them. It has been demonstrated that ubiquitin is covalently associated with insoluble neurofibrillary material of AD-NFTs. Topographical differences in the distribution of NFTs underscore that different neuronal populations including neocortical neurones are affected in progressive supranuclear palsy (PSP) and AD. Differences in the molecular composition of PSP-NFTs highlighted by immunochemical studies induce us to speculate that different physio- and aetiopathogenetic mechanisms are operative in the production of PSP-NFTs.
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PMID:Antigenic determinant properties of neurofibrillary tangles. Relevance to progressive supranuclear palsy. 752 67

Characteristic changes that appear in the biopsied olfactory mucosa of patients with Alzheimer's disease (AD) were examined with immunohistochemical staining. Specimens were obtained from patients with clinical diagnoses of AD. Patients with vascular dementia and age-matched patients without dementia were used for controls. In most AD cases, neurofibrillary tangle-like abnormal tau protein (Tau) immunoreactivity was seen in the dendrites and perikarya of the olfactory receptor cells and in the nerve bundles. A senile plaque-like extracellular mass was found in the olfactory epithelium, and it reacted strongly to an anti-Tau antiserum and weakly to an anti-amyloid-beta protein antiserum. Ubiquitin (Ubq) immunoreactivity was also observed in the dendrites. Tau immunoreactivity of the perikarya and extracellular mass, and Ubq immunoreactivity were especially characteristic of the olfactory mucosa of AD patients. From these results, it is clear that the same pathologic changes in the brain are also present in the olfactory mucosa of patients with AD. Not only disruption of the central olfactory pathway, but also an olfactory disturbance of AD patients is caused by peripheral changes. Furthermore, an olfactory mucosal biopsy could be a useful method for a definitive diagnosis of AD.
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PMID:Pathology of olfactory mucosa in patients with Alzheimer's disease. 820 7

We evaluated by immunohistochemistry the presence of beta-amyloid precursor protein (beta APP) and ubiquitin-like material which may accumulate in axons of the human spinal cord subjected to injury. Autopsy material was obtained from nine cases with different types of trauma: breech delivery with neonatal spinal injury, compression of the cord induced by fractures of the vertebral column, haematomas or intradural meningioma. The posttrauma period ranged from 10 days to several years. The spinal cord of six control cases without evidence of injury presented beta APP immunoreactivity in nerve cell bodies and in a few axonal profiles but not in dendrites. Seven of the nine cases with spinal cord trauma showed an accumulation of beta APP-immunoreactive material in axons of the longitudinal tracts at the site of the injury. Five cases presented similar axonal immunoreactivity in the grey matter of the cord. Ubiquitin-like immunoreactivity was present in expanded axons in cases with spinal cord injury. Cases with spinal cord trauma thus present beta APP-immunoreactive axons particularly of the longitudinal tracts in the same way as in trauma to rat spinal cord and in various brain injuries. The aggregation of beta APP-immunoreactive material indicates disturbed axonal transport of beta APP. Accumulation of ubiquitin-like immunoreactive material in expanded axons at the site of trauma may be one prerequisite for degradation of abnormal proteins by the ubiquitin-mediated proteolytic pathway.
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PMID:Accumulation of beta-amyloid precursor protein and ubiquitin in axons after spinal cord trauma in humans: immunohistochemical observations on autopsy material. 881 Nov 25

Ubiquitin (Ub)-immunocytochemistry on Alzheimer's disease (AD) brain sections shows diverse Ub-associated deposits in the neuropil and senile plaques, elevated levels of Ub reactivity in hippocampal neurons and glia, and co-localization of Ub and beta-amyloid precursor protein (betaPP) epitope reactivity in dystrophic axons. These observations may suggest a role for Ub and stress-related mechanisms in AD pathogenesis. Here we show for the first time that Ub interacts avidly but non-covalently with betaPP and such complexes, apparently formed in vivo, can be isolated from AD brain extracts by Ub-gel matrix affinity chromatography. Polyclonal antibodies specific to Ub and to different regions of betaPP were employed to characterize these proteins. The implication of Ub-betaPP complex formation is discussed in the context of betaPP processing.
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PMID:Ubiquitin (Ub) interacts non-covalently with Alzheimer amyloid precursor protein (betaPP): isolation of Ub-betaPP conjugates from brain extracts. 929 17

Ubiquitin-positive dots and granular structures from insular, temporopolar, hippocampal and parahippocampal cortices of nondemented and Alzheimer's disease patients have been studied with both light and electron microscopes. The relationship of both types of ubiquitin-positive elements with pretangle neurons and neurofibrillary tangles has been analyzed by comparing adjacent or nearly adjacent sections immunostained for either ubiquitin or an antibody that recognizes hyperphosphorylated tau protein (AT-8). Moreover, a double protocol with both antibodies was used in order to obtain double-stained sections. The presence of ubiquitin-positive dots and granular structures precedes the appearance of pretangle neurons in the youngest cases. In aged and Alzheimer disease cases, both types of ubiquitin-positive elements decrease in number as pretangle neurons are replaced by mature and ghost tangles. Ultrastructurally, dots and granular structures appear to be degenerating neuronal processes and/or terminals. Our results suggest that the degeneration of these processes and/or terminals might be related with the initiation of neurofibrillary degeneration.
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PMID:Ubiquitinated granular structures and initial neurofibrillary changes in the human brain. 1170 Nov 49

Two neuropathological changes that are linked with biological and pathological aging were examined in subjects with end-stage acquired immunodeficiency syndrome (AIDS). Autopsy brain specimens were examined from 25 people who died from complications of AIDS and 25 comparison subjects who were human immunodeficiency virus (HIV)-negative, matched for age, gender, ethnicity, and postmortem time interval. These adults were stratified into three age groups: elderly (62 to 75 years), intermediate (55 to 60 years), and young (21 to 42 years). Ubiquitin-stained dotlike deposits (Ub-dots) and diffuse extracellular plaques containing the beta-amyloid (Abeta) fragment of the amyloid precursor protein (Abeta plaque) were both increased significantly in the hippocampal formation of older subjects. In subjects with AIDS, Ub-dots were increased whereas Abeta plaque counts were not significantly different. Western blotting confirmed that high-molecular-weight ubiquitin-protein conjugates (HMW-Ub-conj) were increased in AIDS. The band intensity of one HMW-Ub-conj species with an approximate molecular mass of 145 kDa was correlated significantly with increased acute phase inflammatory protein (a-1-antichymotrypsin) and decreased synaptophysin and growth-associated protein-43 band intensities. These results raise the possibility that HIV-related brain inflammation disturbs neuronal protein turnover through the ubiquitin-proteasome apparatus, and might increase the prevalence of age-associated neurodegenerative diseases by decreasing synaptic protein turnover through the proteasome.
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PMID:Brain aging in acquired immunodeficiency syndrome: increased ubiquitin-protein conjugate is correlated with decreased synaptic protein but not amyloid plaque accumulation. 1520 28

Misfolded and aggregated proteins are a characteristic feature of a variety of chronic diseases. Examples include neurofibrillary tangles in Alzheimer disease, Lewy bodies in Parkinson disease and Mallory bodies (MBs) in chronic liver diseases, particularly alcoholic and non-alcoholic steatohepatitis (ASH and NASH). MB formation is at least in part the result of chronic oxidative cell stress in hepatocytes and can be induced in mice by long-term intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Proteomic analysis revealed that MBs consist of ubiquitinated keratins and the stress proteins Hsp70, Hsp25, and p62. Furthermore, marked overexpression of clusterin, which shares functional properties with small heat shock proteins, was identified by gene expression profiling of DDC-treated mice livers. To investigate whether clusterin has a function in the stress response to misfolded keratins, we performed transfection studies utilizing expression constructs encoding ubiquitin, p62, Hsp27, clusterin, keratin 8, and keratin 18. Ubiquitin was found in a strong and constant association with keratin aggregates, whereas binding of p62 to keratin was variable. Hsp27 did not colocalize with keratin aggregates under these experimental conditions. In contrast, clusterin associated with misfolded keratin only if its signal peptide was deleted and its secretion inhibited. This suggests that clusterin has ability to bind misfolded proteins, including keratins but its physiological function is restricted to the extracellular space. The extracellular localization of clusterin was underlined by immunohistochemical studies in Alzheimer disease brains, where clusterin was constantly found in association with amyloid plaques; in contrast, cytoplasmic inclusions such as neurofibrillary tangles as well as MBs in ASH were negative. Furthermore, we found clusterin in association with elastic fibers in the extracellular matrix in several chronic liver diseases, including ASH and alpha1-antitrypsin deficiency, implying a possible role of clusterin in liver fibrosis.
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PMID:Interaction of stress proteins with misfolded keratins. 1581 11


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