Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0752347 (Dementia with Lewy bodies)
 1,653 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A non-lysosomal multicatalytic proteinase (MCP) is immunohistochemically visualized in Lewy bodies and loosely arranged globose tangles but not in the majority of compact neurofibrillary tangles in brains with cortical diffuse Lewy body disease. Virtually all Lewy bodies are immunoreactive to MCP, exhibiting various staining patterns where they are moderately diffuse, intense in the central core or intense in the peripheral rim. MCP may be involved in the formation of these inclusions.
 ...
PMID:Multicatalytic proteinase is present in Lewy bodies and neurofibrillary tangles in diffuse Lewy body disease brains. 165 33

The ATP-ubiquitin-dependent proteolytic pathway (ubiquitin pathway) is believed to be involved in the formation of various neuronal inclusion bodies including Lewy bodies (LBs), a pathological hallmark of Parkinson disease and diffuse Lewy body disease (DLBD). Since multicatalytic proteinase (MCP) is involved in the ubiquitin pathway, an investigation of whether MCP is involved in neuronal inclusion bodies would provide a clue to the mechanism underlying the formation of neuronal inclusion bodies as well as to the pathogenesis of degenerative neurological disorders. In this study, we investigated detailed immunolocalization of MCP in LBs in DLBD brains using light and electron microscopy. We raised three different monoclonal antibodies against purified human MCP. Each of them recognized different sets of MCP subunits on Western blotting. Immunohistochemically, anti-MCP antibodies recognized all ubiquitin-positive cortical LBs in situ as well as those isolated from frozen DLBD cortices, suggesting that MCP is present in LBs as a whole molecule exhibiting protease activity. In electron microscopy, MCP immunoreactivity (MCP-IR) was exclusively localized on a characteristic oval structure with an approximate diameter of 100 nm. This structure was distributed throughout the LBs and was devoid of ubiquitin immunoreactivity. Treatment of isolated LBs with 2% SDS, but not with 0.5% Triton X-100, removed this structure from LBs in which fibrous materials predominated. Ubiquitin immunoreactivity was also decreased in isolated LBs treated with 2% SDS, suggesting that the fibrous structures in LBs were not ubiquitinated in situ. Thus, it is suggested that LBs are subjected to a proteolytic process in which MCP plays a role via processing of specific components of LBs.
 ...
PMID:Multicatalytic proteinase is associated with characteristic oval structures in cortical Lewy bodies: an immunocytochemical study with light and electron microscopy. 802 94

Lewy bodies (LBs) are the pathological hallmarks of degenerating neurons in the brains of patients with Parkinson's disease and diffuse Lewy body disease. We developed a novel purification procedure for LBs using sucrose density separation followed by fluorescence-activated particle sorting, and we raised > 15 monoclonal antibodies to LBs purified from diffuse Lewy body disease brains. The monoclonal antibody that stained the largest number of LBs most intensely did not recognize ubiquitin in free or monoubiquitinated forms nor the ubiquitin conjugating enzymes, but it did react with polyubiquitin chains as well as with high molecular weight polyubiquitinated LB-derived proteins. Thus, these results suggest that LBs contain polyubiquitin chains. Although polyubiquitination of LB proteins may trigger ubiquitin-proteasome proteolytic pathways, the incomplete activation of these pathways could play a mechanistic role in the formation of LBs in neurodegenerative diseases.
 ...
PMID:Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. 862 21

To determine at the tissue level whether the proteasome (Ps), a unique nonlysosomal protease, is involved in the metabolism of ubiquitinated proteins, we examined for the first time the immunocytochemical localizations of both Ps and ubiquitin (Ub) in sections of various abnormal structures that are known to be ubiquitinated in various neurodegenerative diseases and in the elderly. Concomitant increases of Ps and Ub were observed at the sites of most dystrophic neurites in Alzheimer disease (AD) and parkinsonism-dementia complex on Guam (PDC) and in Lewy bodies in Parkinson's disease and diffuse Lewy body disease, but not in neurofibrillary tangles in AD or PDC, in filamentous inclusions within anterior horn cells in sporadic motor neuron disease, or in eosinophilic granules in the olivary nucleus of the elderly. These results at the tissue level indicated that Ps is involved in the metabolism of some, but not all, ubiquitinated proteins and structures in various neurodegenerative disorders. This suggests that the involvement of Ps in the metabolism of ubiquitinated structures differs in different cases and at different stages of disease. These results and our previous immunocytochemical studies of lysosomal cathepsin proteases suggest that both nonlysosomal and lysosomal systems are involved in the metabolism of various ubiquitinated proteins and that their involvements differ in different structures and at different stages of degeneration of the structures.
 ...
PMID:Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. 903 65

Proteasomal dysfunction has been recently implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and diffuse Lewy body disease. We have developed an in vitro model of proteasomal dysfunction by applying pharmacological inhibitors of the proteasome, lactacystin or ZIE[O-tBu]-A-leucinal (PSI), to dopaminergic PC12 cells. Proteasomal inhibition caused a dose-dependent increase in death of both naive and neuronally differentiated PC12 cells, which could be prevented by caspase inhibition or CPT-cAMP. A percentage of the surviving cells contained discrete cytoplasmic ubiquitinated inclusions, some of which also contained synuclein-1, the rat homologue of human alpha-synuclein. However the total level of synuclein-1 was not altered by proteasomal inhibition. The ubiquitinated inclusions were present only within surviving cells, and their number was increased if cell death was prevented. We have thus replicated, in this model system, the two cardinal pathological features of Lewy body diseases, neuronal death and the formation of cytoplasmic ubiquitinated inclusions. Our findings suggest that inclusion body formation and cell death may be dissociated from one another.
 ...
PMID:Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells. 1152 Sep 10

Molecular misreading of the ubiquitin-B (UBB) gene results in a dinucleotide deletion in UBB mRNA. The resulting mutant protein, UBB+1, accumulates in the neuropathological hallmarks of Alzheimer disease. In vitro, UBB+1 inhibits proteasomal proteolysis, although it is also an ubiquitin fusion degradation substrate for the proteasome. Using the ligase chain reaction to detect dinucleotide deletions, we report here that UBB+1 transcripts are present in each neurodegenerative disease studied (tauo- and synucleinopathies) and even in control brain samples. In contrast to UBB+1 transcripts, UBB+1 protein accumulation in the ubiquitin-containing neuropathological hallmarks is restricted to the tauopathies such as Pick disease, frontotemporal dementia, progressive supranuclear palsy, and argyrophilic grain disease. Remarkably, UBB+1 protein is not detected in the major forms of synucleinopathies (Lewy body disease and multiple system atrophy). The neurologically intact brain can cope with UBB+1 as lentivirally delivered UBB+1 protein is rapidly degraded in rat hippocampus, whereas the K29,48R mutant of UBB+1, which is not ubiquitinated, is abundantly expressed. The finding that UBB+1 protein only accumulates in tauopathies thus implies that the ubiquitin-proteasome system is impaired specifically in this group of neurodegenerative diseases and not in synucleinopathies and that the presence of UBB+1 protein reports proteasomal dysfunction in the brain.
 ...
PMID:Disease-specific accumulation of mutant ubiquitin as a marker for proteasomal dysfunction in the brain. 1459 71

Conjugation of the small ubiquitin-like modifier, SUMO-1, to target proteins is linked to the regulation of multiple cellular pathways, including nucleocytoplasmic trafficking, cell cycle progression, the ubiquitin-proteasome system and apoptosis. Recently, the accumulation of SUMOylated proteins in pathological neuronal intranuclear aggregates has been found in several neurodegenerative diseases. The aim of our study was to examine SUMO-1 in the alpha-synucleinopathy diseases, Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). We conducted anti-SUMO-1 immunostaining of fixed brain tissue sections and smears of unfixed brain tissue homogenates of DLB and MSA cases. We found that oligodendroglial cytoplasmic inclusions, the alpha-synuclein-positive cytoplasmic aggregates that characterize MSA, exhibit robust punctate SUMO-1 immunostaining, marking discrete submicron-sized subdomains within the inclusion bodies. Lewy bodies in smears of DLB tissue homogenates showed similar SUMO-1-positive structures, although these were not detected in fixed tissue. In cell culture experiments, we found that the nuclear and perinuclear accumulation of SUMO-1 aggregates could be induced in glioma cells by chemical inhibition of proteasomal protein degradation.
 ...
PMID:SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy. 1588 93

Alpha-synuclein containing cellular inclusions are a hallmark of Parkinson Disease, Lewy Body Dementia, and Multiple System Atrophy. A genome wide expression screen was performed in C. elegans overexpressing both wild-type and A53T human alpha-synuclein. 433 genes were up- and 67 genes down-regulated by statistical and fold change (> or <2) criteria. Gene ontology (GO) categories within the regulated gene lists indicated over-representation of development and reproduction, mitochondria, catalytic activity, and histone groups. Seven genes (pdr-1, ubc-7, pas-5, pas-7, pbs-4, RPT2, PSMD9) with function in the ubiquitin-proteasome system and 35 mitochondrial function genes were up-regulated. Nine genes that form histones H1, H2B, and H4 were down-regulated. These results demonstrate the effects of alpha-synuclein on proteasome and mitochondrial complex gene expression and provide further support for the role of these complexes in mediating neurotoxicity. The results also indicate an effect on nuclear protein genes that suggests a potential new avenue for investigation.
 ...
PMID:Identification of gene expression changes in transgenic C. elegans overexpressing human alpha-synuclein. 1662 60

Parkinson disease (PD) belongs to a heterogeneous group of neurodegenerative disorders with movement alterations, cognitive impairment, and alpha-synuclein accumulation in cortical and subcortical regions. Jointly, these disorders are denominated Lewy body disease. Mutations in the parkin gene are the most common cause of familial parkinsonism, and a growing number of studies have shown that stress factors associated with sporadic PD promote parkin accumulation in the insoluble fraction. alpha-Synuclein and parkin accumulation and mutations in these genes have been associated with familial PD. To investigate whether alpha-synuclein accumulation might be involved in the pathogenesis of these disorders by interfering with parkin solubility, synuclein-transfected neuronal cells were transduced with lentiviral vectors expressing parkin. Challenging neurons with proteasome inhibitors or amyloid-beta resulted in accumulation of insoluble parkin and, to a lesser extent, alpha-tubulin. Similarly to neurons in the brains of patients with Lewy body disease, in co-transduced cells alpha-synuclein and parkin colocalized and co-immunoprecipitated. These effects resulted in decreased parkin and alpha-tubulin ubiquitination, accumulation of insoluble parkin, and cytoskeletal alterations with reduced neurite outgrowth. Taken together, accumulation of alpha-synuclein might contribute to the pathogenesis of PD and other Lewy body diseases by promoting alterations in parkin and tubulin solubility, which in turn might compromise neural function by damaging the neuronal cytoskeleton. These studies provide a new perspective on the potential nature of pathogenic alpha-synuclein and parkin interactions in Parkinson disease.
 ...
PMID:alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease. 1819 4

Accumulation of proteins in inclusions in neurological disorders is partly due to dysfunction of the ubiquitin-proteasome system. Proteasomal dysfunction may be caused by misexpression of one or more of its subunits. A large number of antibodies reactive with proteasome subunits were screened on material from patients exhibiting tau- and synucleinopathies. Many antisera against proteasomal subunits (11S activator, 19S regulator ATPase/non-ATPase, and 20S alpha and beta resulted in a distinct nuclear and/or cytoplasmic staining of the entorhinal-hippocampal area and the temporal cortex of Alzheimer's disease (AD) patients. In particular an antibody directed against 19S regulator ATPase subunit 6b (S6b) specifically stained the neurofibrillary tangles and dystrophic neurites in AD, Down syndrome and aged nondemented controls. In other tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy and argyrophilic grain disease), neuronal and/or glial inclusions were also S6b immunoreactive. In contrast, in synucleinopathies (Lewy body disease (LBD) and multiple system atrophy) no S6b staining was seen. Real time quantitative PCR on the temporal cortex of AD patients revealed a significant increase in S6b subunit mRNA. This increase was not found in the gyrus cinguli anterior of patients with LBD. This differential expression of S6b most likely will result in different proteomic patterns. Here we present evidence to show that S6b coexists with a reporter for proteasomal dysfunction (ubiquitin(+1)), and we conclude that S6b transcript up-regulation and the dysfunction in tauopathies may be functionally related.
 ...
PMID:Proteasome subunit proteins and neuropathology in tauopathies and synucleinopathies: Consequences for proteomic analyses. 1828 60


1 2 3 Next >>