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At least 397 records · Page 22Linked to original sources
PubMed1986

Tubuloreticular inclusions in placental chorionic villi of rhesus monkeys after maternal treatment with interferon.

Tubuloreticular inclusions were observed in placental chorionic villi of rhesus monkeys after pregnant female monkeys were injected intramuscularly with recombinant leukocyte A interferon (25 X 10(6) units/kg). They were identified in endothelial cells, fibroblasts, and Hofbauer cells of the chorionic villi, providing evidence that interferon crossed at least part of the maternal-fetal partition. Induction of tubuloreticular inclusions in these cells by exogenous interferon has not been previously reported. Tightly packed regular tubular arrangements appeared in endothelial and Hofbauer cells and loosely organized tubular arrays in fibroblasts. The maximum dimension of the tubuloreticular inclusions measured 3 micron and the diameter of the tubules was 20 nm. The tubuloreticular inclusions were continuous with, and surrounded by, smooth endoplasmic reticulum that was often connected to rough endoplasmic reticulum. The tubuloreticular inclusions were not detected in placental chorionic villi from monkeys not treated with interferon or from interferon-treated monkeys 30 days after cessation of treatment. These results indicate that the formation of tubuloreticular inclusions in rhesus monkey placentas was a transient response associated with elevated serum levels of interferon.

Animals↗
PubMed1978

Membranous neuronal and neuroglial inclusions produced by intracerebral injection of Suramin.

A single intracerebral injection of 5 micrometer of the trypanocidal drug Suramin, into the left hemisphere of young rats, resulted in the formation of membranous inclusion bodies within the perikarya and processes of neurones and neuroglia. These inclusion bodies were round or oval in shape and 0.5-3.0 micrometer in their longest diameter. They were bounded by a single trilaminar membrane and contained closely packed membranes in concentric, curved or parallel arrays. The inclusions were distributed throughout the cerebral cortex and underlying hippocampus at the injection site, and in reduced numbers up to 1 mm anteriorly and posteriorly from it. They formed within 22 hr of the injection and had increased in numbers and in the complexity of their arrays 3 days after injection. Within 14 days, the inclusions were markedly reduced in number. As Suramin is known to inhibit lysosomal hydrolases required for the degradation of proteins, glycolipids and mucopolysaccharides, the membranous inclusions could form as a result of the accumulation of these substances within lysosomes. These experiments indicate a possible experimental model for storage diseases. It is hoped that the extension of this paradigm to other enzyme inhibitors will provide a new means of identifying some of the unusual inclusions that can be found in neurones and neuroglia (Rees 1975).

Animals↗
PubMed1993

Cytoplasmic inclusions in spinal neurons of the motor neuron degeneration (Mnd) mouse. I. Light microscopic analysis.

The motor neuron degeneration (Mnd) mutation in the mouse is a late onset, autosomal dominant, neurodegenerative disease in which ventral horn neurons have been shown to contain numerous, large cytoplasmic inclusions. Histochemical and immunocytochemical studies performed on spinal cord from Mnd/Mnd mice in late stages of the disease showed the inclusions to contain protein, lipid and carbohydrate moieties. Spinal neurons, especially those in spinal lamina IX, contained increased beta-glucuronidase activity in the form of large cytoplasmic inclusions. Such inclusions also contained increased acid phosphatase and trimetaphosphatase activity. When immunostained with antiubiquitin antibodies, intracellular ubiquitin deposits were present as accumulations of varying size; some were amorphous while others contained small granules. Extraneuronal ubiquitin deposits were detected in the neuropil. Immunostaining with monoclonal antibody ML30, used here to assay for the presence of a mitochondrial epitope in the inclusions, was widespread and punctate in white and grey matter from Mnd/Mnd and age-matched control spinal cords. The overall pattern of staining was similar for both tissue sources and did not correspond to any of the other probes which reacted with the inclusions in Mnd neurons. The presence of increased levels of lysosomal hydrolases and ubiquitinated molecules suggests that the two general systems for intracellular digestion are activated in Mnd/Mnd spinal neurons.

Animals↗
PubMed1995

Vitamin A incorporation into lipofuscin-like inclusions in the retinal pigment epithelium.

Intravitreal injection of the protease inhibitor leupeptin causes a rapid accumulation of lipofuscin-like autofluorescent inclusions in the retinal pigment epithelium (RPE) of the eye. In vitamin A-deprived animals, similar inclusions form in response to leupeptin treatment, but they do not become autofluorescent. Because vitamin A is necessary to the development of fluorescence, it appears likely that retinoids are directly incorporated into the inclusions. Experiments were conducted to determine whether this is the case. Rats were reared on a diet containing retinoic acid as the only retinoid. Retinoic acid cannot be utilized in visual transduction by the retina. When the eyes had been over 90% depleted of visual cycle retinoids, the animals were given a single intramuscular injection of 3H-all-trans retinol. After 7 days, when visual cycle retinoids had returned to an average of almost 70% of normal, the animals were given an intravitreal injection of leupeptin in each eye. At either 1 day or 7 days after the leupeptin treatment, some of the animals were dark-adapted for at least 12 h. The eyes were enucleated and fixed under dim red light. A region of each retina just superior to the optic nerve head was examined with electron microscopic autoradiography. At both one day and 7 days after the leupeptin treatment, the radiolabel in the RPE was primarily associated with the leupeptin induced inclusion bodies. Label was also present in the photoreceptor outer segments. The localization of vitamin A to the leupeptin-induced inclusions in the RPE strongly suggests that vitamin A is covalently bound to outer segment proteins that have been phagocytosed by the RPE but remain undegraded due to protease inhibition. This bound vitamin A is probably responsible for the autofluorescence of the leupeptin-induced inclusions. Vitamin A is not likely to be bound through a Schiff base linkage, since retinal-Schiff base compounds do not exhibit lipofuscin-like fluorescence.

Animals↗
PubMed1995

Rimmed basophilic vacuoles and filamentous inclusions in neuromuscular disorders.

To study the incidence of rimmed basophilic vacuoles (RBV) and 15-21 nm filamentous inclusions in neuromuscular disorders, other than inclusion body myositis (IBM) and to determine the diagnostic value of RBV quantitation in the differential diagnosis of IBM, we reviewed 1600 muscle biopsies for RBV and 750 biopsies for filamentous inclusions. The number of RBV-positive fibers per 10 mm2--the RBV-fiber density--was determined. The incidence of RBV in non-IBM biopsies was 8.8 per 1000. Major diagnostic categories were neurogenic disorders (n = 7) and limb girdle muscular dystrophies (LGMD) (n = 3). In IBM (n = 7) the RBV-fiber density ranged from 10.4 to 63.1 and was significantly higher than in neurogenic disorders (0.9-4.4) and LGMD (1.1-2.7). The highest value was found in rigid spine syndrome (205.8). Filamentous inclusions were seen in 2.7 per 1000 non-IBM biopsies, including familial oculopharyngeal muscular dystrophy with distal myopathy (OPMD-DM), rigid spine syndrome, acid maltase deficiency and amyloid neuropathy. RBV and filamentous inclusions coexisted in rigid spine syndrome and in familial OPMD-DM. RBV, as well as filamentous inclusions, has a very low incidence in non-IBM neuromuscular disorders; the RBV-fiber density may help to discriminate neurogenic disorders and LGMD from IBM.

Adolescent↗
PubMed2005

Evidence for sequestration of polyglutamine inclusions by Drosophila myeloid leukemia factor.

Intracellular inclusions of abnormally long polyglutamine tracts and neurotoxicity are the hallmarks of several hereditary neurodegenerative disorders, including Huntington's disease (HD). In Drosophila melanogaster, dMLF, an ortholog of human myeloid leukemia factors, hMLF1 and hMLF2, suppressed polyglutamine toxicity and colocalized with the inclusions. In transfected primary rat neuronal cultures, dMLF and its orthologs reduced the morphological phenotypes and inclusions. Furthermore, dMLF reduced the recruitment of CBP and Hsp70 into the inclusions, both of which are among many essential proteins apparently trapped in the inclusions. These data suggest that a possible mechanism of suppression by dMLF is via the sequestration of polyglutamine oligomers or inclusions.

Animals↗
PubMed2005

Preservation of in vitro muscle fiber function in dermatomyositis and inclusion body myositis: a single fiber study.

Five patients with untreated dermatomyositis, five with inclusion body myositis, and 16 healthy elderly volunteer subjects (controls) underwent open (dermatomyositis and inclusion body myositis) or percutaneous (controls) muscle biopsy. Biopsied muscles included deltoid, biceps and vastus lateralis. Chemically skinned single muscle fibers were activated with Ca(+2); the slack test was performed to determine maximal unloaded shortening velocity (Vo). Parameters measured include single fiber cross sectional area, maximal force, specific force and Vo. 429 Type I and 94 Type IIA fibers were studied. Cross sectional area and maximal force were greater in inclusion body myositis than dermatomyositis or control for Type I and IIA fibers. Specific force of Type I fibers was similar in inclusion body myositis and dermatomyositis but greater than in controls. Vo was greater in Type I, but not IIA, fibers in dermatomyositis compared with inclusion body myositis and controls. The force and velocity generating capacity of single muscle fibers is preserved in patients with dermatomyositis and inclusion body myositis suggesting that dysfunction of the contractile proteins does not contribute to clinical muscle weakness.

Adult↗
PubMed2000

Basophilic cytoplasmic inclusions in a case of sporadic juvenile amyotrophic lateral sclerosis.

A 24-year-old woman presented with progressive muscle atrophy and weakness of the right upper extremity. Subsequently her weakness rapidly extended to the left upper extremity, neck and lower extremities. Neurological examination disclosed involvement of the lower motor neuron system. She died 7 months after the onset. There was neuronal loss and reactive gliosis in the anterior horns of the spinal cord and much less frequently in the motor cortex. Basophilic cytoplasmic inclusions were observed in the thalamus and brain stem as well as the upper and lower motor neurons. Ultrastructurally, the inclusions lacked a limiting membrane and consisted of a meshwork of filamentous structures associated with granules. The inclusions failed to react with antibodies against phosphorylated neurofilament or cystatin C. Most of the inclusions show no reaction with anti-ubiquitin antibody, however, a few inclusions show granular reaction product deposits with this antibody. The inclusions were not immunostained with antibodies against TGN46 and MG-160, markers of the trans-Golgi network and the medial cisternae of the Golgi apparatus, respectively, suggesting that they were not derived from the Golgi apparatus which was fragmented.

Adult↗
PubMed2003

DnaK and DnaJ facilitated the folding process and reduced inclusion body formation of magnesium transporter CorA overexpressed in Escherichia coli.

Overexpression of CorA, the major magnesium transporter from bacterial inner membrane, in Escherichia coli resulted in the synthesis of 60mg of protein per liter of culture, most of which however was in the form of inclusion bodies. The levels of inclusion body formation were reduced by lowering the cell culture temperature. To dissect CorA inclusion body formation and the folding process involved, we co-expressed the protein with various chaperones and other folding modulators. Expression of DnaK/DnaJ (Hsp70) prevented inclusion bodies from forming and resulted in the integration of more CorA into the membrane. GroEL/GroES (Hsp60/Hsp10) were less effective at reducing CorA inclusion body formation. Co-expression with either Ffh/4.5S-RNA, the signal recognition particle, or SecA, the ATPase that drives protein insertion into the membrane, had little effect on CorA folding. These results indicate: (1) that CorA inclusion bodies form immediately after synthesis at 37 degrees C, (2) that CorA solubility in the cytosol can be increased by co-expressing a chaperone system, (3) membrane targeting is probably not a rate-limiting factor, and (4) that membrane insertion becomes a limitation only when large amounts of soluble CorA are present in the cytosol. These co-expression systems can be used for producing other membrane proteins in large quantities.

Cation Transport Proteins↗
PubMedDate not supplied

Physicochemical characteristics of LR3-IGF1 protein inclusion bodies: electrophoretic mobility studies.

A knowledge of the physicochemical properties of inclusion bodies is important for the rational design of potential recovery processes such as flotation and precipitation. In this study, measurement of the size and electrophoretic mobility of protein inclusion bodies and cell debris was undertaken. SDS-PAGE analysis of protein inclusion bodies subjected to different cleaning regimes suggested that electrophoretic mobility provides a qualitative measure of protein inclusion body purity. Electrophoretic mobility as a function of electrolyte type and ionic strength was investigated. The presence of divalent ions produced a stronger effect on electrophoretic mobility compared with monovalent ions. The isoelectric point of cell debris was significantly lower than that for the inclusion bodies. Hence, the contaminating cell debris may be separated from inclusion bodies using flotation by exploiting this difference in isoelectric points. Separation by this method is simple, convenient, and a possible alternative to the conventional route of centrifugation.

Electrophoresis, Polyacrylamide Gel↗
PubMed2004

Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death.

Huntington's disease is caused by an abnormal polyglutamine expansion within the protein huntingtin and is characterized by microscopic inclusion bodies of aggregated huntingtin and by the death of selected types of neuron. Whether inclusion bodies are pathogenic, incidental or a beneficial coping response is controversial. To resolve this issue we have developed an automated microscope that returns to precisely the same neuron after arbitrary intervals, even after cells have been removed from the microscope stage. Here we show, by survival analysis, that neurons die in a time-independent fashion but one that is dependent on mutant huntingtin dose and polyglutamine expansion; many neurons die without forming an inclusion body. Rather, the amount of diffuse intracellular huntingtin predicts whether and when inclusion body formation or death will occur. Surprisingly, inclusion body formation predicts improved survival and leads to decreased levels of mutant huntingtin elsewhere in a neuron. Thus, inclusion body formation can function as a coping response to toxic mutant huntingtin.

Animals↗
PubMed2001

Formation of advanced glycation end-product-modified superoxide dismutase-1 (SOD1) is one of the mechanisms responsible for inclusions common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutation, and transgenic mice expressing human SOD1 gene mutation.

Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) are morphological hallmarks of certain familial amyotrophic lateral sclerosis (FALS) patients with superoxide dismutase-1 (SOD1) gene mutations, and transgenic mice expressing the human SOD1 gene mutation. The ultrastructure of inclusions in both diseases is identical: the essential common constituents are granule-coated fibrils approximately 15-25nm in diameter and granular materials. Detailed immunohistochemical analyses have shown that the essential common protein of the inclusions in both diseases is an SOD1 protein. This finding, together with the immunoelectron microscopy finding that the abnormal granule-coated fibrils comprising the inclusions are positive for SOD1, indicates that these granule-coated fibrils containing SOD1 are important evidence for mutant SOD1-linked disease in human and mouse. For immunoelectron microscopy, the granule-coated fibrils are modified by advanced glycation endproducts (AGE) such as N(epsilon)-carboxymethyl lysine, pyrraline and pentosidine (Maillard reaction). Based on the fact that AGE themselves are insoluble molecules with direct cytotoxic effects, the granule-coated fibrils and granular materials are not digested by the lysosomal and ubiquitin systems. The neurons and astrocytes of the normal individuals and non-transgenic mice show no significant immunoreactivity for AGE. Considered with the mutant-SOD1 aggregation toxicity, a portion of the SOD1 comprising both types of the inclusion is modified by the AGE, and the formation of the AGE-modified SOD1 (probably AGE-modified mutant SOD1) is one of the mechanisms responsible for the aggregation (i.e. granule-coated fibril formation).

Amyotrophic Lateral Sclerosis↗
PubMed2002

Identification of an aging-related spherical inclusion in the human brain.

Inclusions, such as corpora amylacea, axonal spheroids and ubiquitin-positive granular structures, are present in aged brains. We found a phosphorylated tau-positive inclusion in brain tissues obtained from 13 non-demented subjects and five patients with Alzheimer's disease. This inclusion was spherical and 3-20 microm in size. It was most frequently detected in the hippocampal CA1 region and in the prosubiculum but was not present in the white matter. The density of this inclusion increased significantly with aging and decreased after the occurrence of neurofibrillary tangles. The presence of the inclusion was confirmed using immunoelectron microscopy. These findings show a possibility that the inclusion is a novel aging-related structure in the human brain.

Adult↗
PubMed2006

Ground-glass, polyglucosan-like hepatocellular inclusions: A "new" diagnostic entity.

BACKGROUND & AIMS: Ground-glass (GG) inclusions within hepatocytes are an important histopathologic marker of chronic hepatitis B virus (HBV) infection but may also be seen in Lafora's disease (myoclonus epilepsy), cyanamide alcohol aversion therapy, and type IV glycogenosis. We have noted a recent increased incidence of liver biopsy and postmortem specimens with GG inclusions associated with none of these etiologic factors. This study was undertaken to further delineate the clinical and liver pathologic features in such cases and their possible pathogenesis. METHODS: Ten cases with GG inclusions (8 biopsy, 2 postmortem) were examined by light and electron microscopy, and the patients' clinical records were reviewed. RESULTS: Light microscopy demonstrated pale pink, oval to crescentic intracytoplasmic inclusions with a predilection for periportal hepatocytes but sometimes present throughout the lobules. The inclusions were intensely positive on periodic acid-Schiff stain and digested with diastase. Transmission electron microscopy of two cases showed non-membrane-bound cytoplasmic collections of granules with mild-to-moderate electron density, consistent with abnormal glycogen granules. The patients included 7 transplant recipients (liver, hematopoietic stem cell), 3 with type 2 diabetes and a child on chronic parenteral nutrition for short bowel syndrome. Medications included immunosuppressive agents, antibiotics, and insulin. CONCLUSIONS: GG hepatocellular inclusions may be seen in individuals without HBV infection or other recognized etiologies, appear to be composed of abnormal glycogen and closely resemble polyglucosan bodies described in humans, animals, and experimental models. The possible pathogenetic roles of disturbed glycogen metabolism and polypharmacotherapy are stressed.

Adolescent↗
PubMed1986

Development of the smooth muscle foam cell: uptake of macrophage lipid inclusions.

A possible mechanism for the formation of smooth muscle foam cells in the atherosclerotic lesion was explored. Cultured macrophages (J774 cell line) were induced to form cytoplasmic cholesteryl ester inclusions by exposure to acetylated low density lipoprotein in the presence of cholesterol-rich phospholipid dispersions. The macrophages were disrupted by brief sonication, and the inclusions were isolated by flotation. When these inclusions were placed in direct contact with cultured smooth muscle cells, cellular uptake of the inclusions in a time- and dose-dependent manner was observed. Light and electron microscopy indicated the presence of lipid inclusions throughout the cytoplasm of the cells. Uptake of inclusion lipid by the smooth muscle cells was inhibited by several metabolic inhibitors, indicating that the process is dependent on metabolic activity. A modest but significant hydrolysis of the cholesteryl ester was observed, showing that the stored cholesteryl esters are metabolically available.

Arteriosclerosis↗
PubMed2002

Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is one of a group of progressive neurodegenerative diseases resulting from a polyglutamine repeat expansion. In SBMA the polymorphic trinucleotide CAG repeat in exon 1 of the androgen receptor (AR) gene is increased, resulting in expansion of a polyglutamine tract. Patient autopsy material reveals neuronal intranuclear inclusions (NII) in affected regions that contain only amino-terminal epitopes of the AR. Cell models have previously been unable to produce intranuclear inclusions containing only a portion of the AR. We report here the creation of an inducible cell model of SBMA that reproduces this important characteristic of disease pathology. PC12 cells expressing highly expanded AR form ubiquitinated intranuclear inclusions containing amino-terminal epitopes of the AR as well as heat shock proteins. Inclusions appear as distinct granular electron-dense structures in the nucleus by immunoelectron microscopy. Dihydrotestosterone treatment of mutant AR-expressing cells results in increased inclusion load. This model mimics the formation of ubiquitinated intranuclear inclusions containing the amino-terminal portion of AR observed in patient tissue and reveals a role for ligand in the pathogenesis of SBMA.

Animals↗
PubMed1998

Sporadic inclusion-body myositis and its similarities to Alzheimer disease brain. Recent approaches to diagnosis and pathogenesis, and relation to aging.

Sporadic inclusion-body myositis (s-IBM) is the most common, debilitating and progressive muscle disease beginning at the age 50 or later. The most characteristic pathologic feature is vacuolar degeneration of muscle fibers accompanied by intrafiber congophilia and clusters ("tangles") of paired-helical filaments, containing phosphorylated tau. An unusual feature of sporadic inclusion-body myositis is accumulation within its abnormal muscle fibers of several proteins that are characteristic of Alzheimer disease brain, including epitopes of beta-amyloid precursor protein (betaAPP), phosphorylated tau, alpha-1-antichymotrypsin, apolipoprotein E, and presenilin-1. Indicators of oxidative stress are also present within abnormal s-IBM muscle fibers. In this review, we describe new advances seeking the pathogenic mechanism of sporadic inclusion-body myositis. We hypothesize on the possible pathogenic role of abnormally accumulated proteins, and we propose that important contributory factors leading to inclusion-body myositis are the milieu of muscle-fiber aging and oxidative stress. In addition, we present evidence that overexpression of adenovirus-transferred betaAPP gene in cultured human muscle fibers induces aspects of the inclusion-body myositis phenotype, and suggest that betaAPP-overexpression is an early event in the pathogenic cascade causing inclusion-body myositis.

Alzheimer Disease↗
PubMed2001

Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation.

The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human 293 Tet-Off cells. These structures contain aggregated, ubiquitinated huntingtin exon 1 protein with a characteristic fibrillar morphology. Inclusion bodies with truncated huntingtin protein are formed at centrosomes and are surrounded by vimentin filaments. Inhibition of proteasome activity resulted in a twofold increase in the amount of ubiquitinated, SDS-resistant aggregates, indicating that inclusion bodies accumulate when the capacity of the ubiquitin-proteasome system to degrade aggregation-prone huntingtin protein is exhausted. Immunofluorescence and electron microscopy with immunogold labeling revealed that the 20S, 19S, and 11S subunits of the 26S proteasome, the molecular chaperones BiP/GRP78, Hsp70, and Hsp40, as well as the RNA-binding protein TIA-1, the potential chaperone 14-3-3, and alpha-synuclein colocalize with the perinuclear inclusions. In 293 Tet-Off cells, inclusion body formation also resulted in cell toxicity and dramatic ultrastructural changes such as indentations and disruption of the nuclear envelope. Concentration of mitochondria around the inclusions and cytoplasmic vacuolation were also observed. Together these findings support the hypothesis that the ATP-dependent ubiquitin-proteasome system is a potential target for therapeutic interventions in glutamine repeat disorders.

14-3-3 Proteins↗