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PubMed2003

Glandular inclusions in inguinal hernia sacs: morphologic and immunohistochemical distinction from epididymis and vas deferens.

Glandular inclusions in inguinal hernia sacs may bear a striking resemblance to the epididymis or vas deferens. Misinterpretation as a transected functional structure may raise significant concerns regarding reproductive capability, even if encountered unilaterally. In a child, resolution of these concerns may be years away with the onset of puberty and documentation of normal sperm counts. CD10 has been shown to be present in Wolffian-type epithelium and to be absent in Mullerian-type epithelium. We hypothesized that an antibody to CD10 would react with vas deferens and epididymis and fail to react with hernia sac inclusions, most of which we thought were Mullerian duct-derived structures. Glandular inclusions in 29 hernia sacs from prepubertal males were classified histologically according to their resemblance to normal structures and analyzed for CD10 by immunohistochemistry. Inclusions resembling vas deferens had their external diameters measured and were also stained for smooth muscle actin. Thirty-one examples of normal vas deferens and 13 examples of normal epididymis were included for comparison. The inclusions were classified as vas deferens-like (9), epididymis-like (13), and Mullerian-like (7). CD10 reactivity was lacking in all vas deferens-like inclusions; their median external diameter was 0.6 mm. Of the epididymis-like inclusions, 7 of 13 were CD10 positive. The CD10-negative cases consisted of glands with well-defined stromal coats distinct from adjacent stromal coats. CD10-positive cases were more numerous, more tightly aggregated, and surrounded by less well-developed stromal coats that blended with adjacent coats. All seven Mullerian-like remnants were CD10 negative. All normal vas deferens and epididymis showed at least focal CD10 reactivity. CD10 positivity in all cases had a luminal membranous staining pattern. Both the vas deferens-like inclusions and the normal vas deferens showed strong smooth muscle actin positivity in their stromal coats. CD10 negativity and external diameter <1 mm are highly useful to distinguish vas deferens-like inclusions from true vas deferens. Epididymis-like inclusions are more problematic. Some react for CD10 and may represent aberrant Wolffian ductules. Others are CD10 negative, distinct from true epididymis, and may be of Mullerian differentiation. Mullerian-like remnants can be diagnosed on the basis of their limited number and scattered distribution. Lack of CD10 immunostaining corroborates this interpretation.

Adolescent↗
PubMed2006

Inclusive trauma systems: do they improve triage or outcomes of the severely injured?

BACKGROUND: Trauma systems decrease injury-related mortality, but not all systems have the same configuration. In some systems, nearly all acute care hospitals participate to the extent that their resources allow (inclusive systems), whereas in others, relatively few high-level centers participate (exclusive systems). We postulate that inclusive systems assure that severely injured patients are more likely to be triaged to a level I or II regional trauma center, and this greater degree of participation would lead to lower mortality. METHODS: We used administrative discharge data for 2001 in 24 states with formal systems, and we included all urgently hospitalized adults with an Injury Severity Score>or=16. We categorized states by trauma system configuration ("exclusive", "more inclusive", "most inclusive") based on the proportion of all hospitals designated as a Level I through V trauma center (0-13%, 14-37%, 38-100%, respectively). We compared the rates of triage to a regional trauma center and inpatient death in inclusive states relative to exclusive states, while adjusting for patient- and state-level factors. RESULTS: Out of 61,496 patients, 40,706 (66.2%) were hospitalized at regional trauma centers. Inpatient mortality was 14.7%. After adjusting for patient age, primary payer status, and system maturity, the odds of triage to a regional trauma center were similar in inclusive and exclusive systems. After adjusting for primary payer status, mechanism of injury, and system maturity, the odds of death were similar in more inclusive and exclusive systems (odds ratio, 0.93; 95% confidence interval, 0.80-1.08) but were significantly lower in the most inclusive systems (odds ratio, 0.77; 95% confidence interval, 0.60-0.99). CONCLUSIONS: Severely injured trauma patients have greater inpatient survival in inclusive trauma systems even though they are no more likely to be hospitalized at a regional trauma center. Consideration should be given to continuing implementation of systems with an inclusive configuration, especially in light of other theoretical benefits of these systems, such as better dispersing of trauma care resources in the event of natural disasters or terrorist events.

Adult↗
PubMed2006

Coupling between vesicle shape and lateral distribution of mobile membrane inclusions.

Membrane inclusions such as membrane-embedded peptides or proteins exhibit a curvature-dependent interaction with the surrounding lipid matrix due to the mismatch between their intrinsic curvature and the local membrane curvature. This interaction causes an inhomogeneous lateral distribution of the inclusions and a corresponding adjustment of the vesicle shape. We have studied theoretically the axisymmetric equilibrium shapes of lipid vesicles with mobile inclusions, taking into account that the membrane free energy includes the elastic energy of the lipid bilayer and a contribution due to an inclusion-membrane interaction. Equations describing the shape are derived by minimizing the total free energy at fixed membrane area, enclosed volume, and number of inclusions and are then solved numerically. It is shown that vesicle shape may assume a symmetry that differs from that of the vesicle with no inclusions. If the inclusion-membrane interaction exceeds a certain value, there is no axisymmetric solution of the equations with a continuous and derivable lateral density of inclusions over the whole area of the vesicle. When approaching the critical vesicle shape, the shapes obtained differ qualitatively from those described by the area difference elasticity model of the elastic properties of lipid membranes. In general, vesicle shapes adjust to the presence of inclusions by increasing regions with favorable curvature and decreasing regions of unfavorable curvature in a way such that the lateral distribution of inclusions becomes inhomogeneous.

Cell Membrane↗
PubMed2002

Inclusion fluorescent-antibody test as a screening assay for detection of antibodies to Chlamydia pneumoniae.

A study was conducted to determine the ability of the inclusion immunofluorescence assay (inclusion IFA) to act as a screening test to detect samples with antibodies to Chlamydia pneumoniae; microimmunofluorescence (MIF) was used as the "gold standard." In addition, the inclusion IFA was compared using HEp-2 cells infected with either C. pneumoniae CM-1 or Chlamydia trachomatis serovar E. A total of 331 serum samples representing a range of MIF titers were evaluated. The sensitivities of the inclusion IFA for detecting samples with C. pneumoniae MIF titers of > or = 16 were 96.9 and 74.8% with C. pneumoniae- and C. trachomatis-infected cells, respectively. For samples with an elevated C. pneumoniae MIF titer of > or = 512, the sensitivities of the C. pneumoniae- and C. trachomatis-based inclusion IFA were 97.0 and 8.8%, respectively. These results suggest that the inclusion IFA is not a genus-specific test, as evidenced by the failure of the C. trachomatis-infected cells to detect a significant number of samples with C. pneumoniae antibodies. Samples that had elevated C. pneumoniae inclusion IFA and MIF titers but that were found negative (titer, <16) by the C. trachomatis inclusion IFA were further tested by an in vitro neutralization assay for functional antibodies that might not have been detected by the serological assays. The in vitro neutralization results corroborated the serological results in that all seven sera tested had a neutralization titer for C. pneumoniae (range, 20 to 225), while all but one failed to have any effect on the infectivity of C. trachomatis serovar E. While the C. pneumoniae inclusion IFA had a high sensitivity for detecting chlamydial antibodies, depending on whether it was used as a screening test for detecting samples with low (> or = 16) or elevated (> or = 512) MIF titers, its specificity ranged from 53.4 to 77.1%. In conclusion, the inclusion IFA with C. pneumoniae-infected cells was best suited as a sensitive screening test for identifying specimens with elevated MIF titers (those associated with a possible acute infection with C. pneumoniae).

Adult↗
PubMed1987

Protein inclusions produced by the entomopathogenic bacterium Xenorhabdus nematophilus subsp. nematophilus.

The entomopathogenic bacterium Xenorhabdus nematophilus subsp. nematophilus produces two types of intracellular inclusion bodies during in vitro culture. Large cigar-shaped inclusions (designated type 1) and smaller ovoid inclusions (designated type 2) were purified from cell lysates, using differential centrifugation in discontinuous glycerol gradients and isopycnic density gradient centrifugation in sodium diatrizoate. The inclusions, composed almost exclusively of protein, are readily soluble at high and low pH values and in the presence of cation chelators such as EDTA, anionic detergents (sodium dodecyl sulfate), or protein denaturants (urea, NaBr). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of purified inclusions revealed a single 26-kilodalton protein (IP-1) in type 1 inclusions and a 22-kilodalton protein (IP-2) in type 2 inclusions. Analysis of these proteins by isoelectric focusing in the presence of 8 M urea showed that IP-1 is acidic and IP-2 is neutral. Furthermore, each protein occurred in multiple forms differing slightly in isoelectric point. Other variations in peptides released by trypsin digestion, immunological properties, and amino acid composition revealed significant structural differences between IP-1 and IP-2. Kinetic studies using light microscopy, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunoblotting procedures showed that inclusion protein synthesis occurs only during the second half of exponential culture growth. Synthesis of inclusion proteins and their aggregation to form inclusions occurred concurrently. Possible functions for these abundant proteins are discussed.

Amino Acids↗
PubMed1983

Cellular cholesteryl ester clearance. Relationship to the physical state of cholesteryl ester inclusions.

The hypothesis that clearance of cellular cholesteryl ester deposits may be a function of the physical state of the stored lipid has been investigated. Cultured rat hepatoma cells were induced to store cholesteryl ester in either anisotropic inclusions by exposure to free cholesterol-rich phospholipid dispersions or isotropic inclusions by exposure to identical dispersions supplemented with oleic acid. Differential scanning calorimetry demonstrated an order/disorder transition at 43 degrees C for cholesteryl esters stored in anisotropic inclusions; the enthalpy of this transition was consistent with a smectic liquid crystalline to liquid transition. Lipids in cells with isotropic inclusions displayed no order/disorder transitions over the range 20-80 degrees C, indicating that the lipids are in a liquid state. The presence of oleic acid did not influence the mass of cholesteryl ester stored but increased the amount of stored triglyceride. Fatty acyl compositions of the cholesteryl esters were different under the two loading conditions; in particular, there was 38% cholesteryl oleate in anisotropic inclusions and 65% cholesteryl oleate in isotropic inclusions. Kinetics of cholesteryl ester clearance from cells with either anisotropic or isotropic inclusions were studied during a 12-h exposure to acceptors of free cholesterol. In both cases, cholesteryl ester clearance is essentially linear over 12 h and is directly proportional to the initial content of cholesteryl ester. However, the fraction of initial content of cholesteryl ester cleared in 12 h is 0.17 +/- 0.05 for cells with anisotropic inclusions and 0.34 +/- 0.09 for cells with isotropic inclusions. Our data demonstrate that the more rapid clearance of cholesteryl ester by cells with isotropic inclusions can be correlated with the physical state of the cholesteryl ester.

Animals↗
PubMed1981

The intranuclear filamentous inclusions of a human glioma. Their relation with nuclear bodies.

The intranuclear filamentous inclusions of a human glioma were analysed with an electron microscope equipped with a goniometer stage. The inclusions consist of 6 to 8 filaments. Considering the organization of the constituent filaments we distinguish three basic types: 1. Filamentous bundles of more or less parallel filaments, forming a cigarshaped inclusion. 2. Crystalloid inclusions: a. Prisms. They consist of stacked layers of strictly parallel filaments. The angle formed by the filaments of adjacent layers if 60 degrees. b. Cylinders. The layers of filaments are bent up and may form either a circle or a spiral, when the inclusion is seen in cross-section. 3. Partially crystalloid or "intermediate" inclusions. We consider them to be transitional forms between types 1 and 2 inclusions. The crystalloid layers of such intermediate inclusions may form either prisms or cylinders. Finally, the similarity between the granulo-fibrillar capsules surrounding granular nuclear bodies and filamentous inclusions, as well as the existence of granular material dispersed between the filaments of some inclusions led us to investigate a relationship between these two structures.

Brain Neoplasms↗
PubMed1977

Mitochondrial inclusions in human cancer of the gastrointestinal tract.

Four cases of adenocarcinoma of the gastrointestinal tract have been examined. Large electron-dense mitochondrial inclusions were found in the mitochondria of many cells; after detailed histochemical tests they could be classified into two types. The first type of inclusion consisted of clusters of electron-dense, calcium-containing granules linked to a glycoproteic substrate. These inclusions were linked to a glycoproteic substrate. These inclusions were always associated with cristae and were found in the mitochondria of cells that showed clear signs of degeneration. The second type of inclusion was found much more frequently and consisted essentially of phospholipids of which electron density was strictly osmium dependent. Their structure was usually at least partly lamellar, but in some cases it was homogeneous throughout. It is hypothesized that inclusions of the second type may have the same biological role as the morphologically identical inclusions found in the mitochondria of brown fatty tissue in the perinatal rat and in yeasts during glucose repression or anaerobiosis. The resemblance between the homogeneous variety of inclusions within the second type and the mitochondrial inclusions recently described in human leukemic lymphoblasts and monoblasts has been stressed to bring out the need for a histochemical check on the supposedly viral nature of the latter inclusions.

Adenocarcinoma↗
PubMed2001

Smooth muscle inclusion bodies in slow transit constipation.

Slow transit constipation (STC) is a disorder of intestinal motility of unknown aetiology. Myopathies, including those characterized by the finding of inclusion bodies, have been described in enteric disorders. Amphophilic inclusion bodies have been reported in the muscularis externa of the colon of STC patients. This study formally tested the hypothesis that these represent a primary muscle disorder, specific to STC. In a systematic, blinded, dual observer qualitative and quantitative analysis, colonic and ileal tissue from patients with STC (n=36) were compared with selected control populations: total colonic aganglionosis (n=10), Chagas' disease (n=6), isolated rectal evacuation disorders (n=6), and a control population of a range of ages (n=80). All sections were stained with haematoxylin and eosin and periodic acid Schiff. Further immunostains were used in an attempt to determine inclusion body composition. Round or ovoid (4-22 microm diameter) amphophilic inclusions increased in number in normal subjects with age. Inclusions were more frequent in idiopathic STC than in age-matched controls or rectal evacuation disorders [ileum (33% vs. 9%), ascending (50% vs. 19%, p<0.05), and sigmoid colon (43% vs. 20%)] and were very frequent in the sigmoid (71%) of patients with STC arising after pelvic surgery. The number of inclusions per unit area was significantly higher in patients with STC (p<0.001). Inclusions were found in all Chagas' patients, but not with aganglionosis. It was not possible to determine inclusion body composition, despite the use of a wide range of conventional and immunostains. This study demonstrates that inclusion body myopathy is identifiable in patients with STC and that it may arise secondary to denervation.

Adult↗
PubMed1996

Apolipoprotein E and apolipoprotein E messenger RNA in muscle of inclusion body myositis and myopathies.

Sporadic inclusion body myositis and the hereditary inclusion body myopathies are severe, progressive muscle diseases, characterized pathologically by vacuolated muscle fibers containing paired helical filaments. We immunostained muscle biopsy specimens from sporadic inclusion body myositis, hereditary inclusion body myopathy, disease control, and normal patients with several antibodies against apolipoprotein E (ApoE). Approximately 80 to 90% of the vacuolated muscle fibers of sporadic inclusion body myositis contained well-defined, strongly immunoreactive ApoE inclusions. In hereditary inclusion body myopathy, only rare vacuolated fibers had immunoreactive inclusions, whereas most had diffuse cytoplasmic ApoE immunoreactivity. Ultrastructurally, ApoE immunoreactivity in sporadic myositis was localized mainly to the paired helical filaments. By contrast, in the hereditary form, ApoE immunoreactivity occurred on material in close proximity to the paired helical filaments, but never was on the paired helical filaments. In both muscle diseases, ApoE was also on the 6- to 10-nm filaments and amorphous material. In the sporadic form, ApoE-immunoreactive deposits colocalized with Congo red-positive deposits; however, in muscle fibers from patients with hereditary disease there was no congophilia. ApoE messenger RNA was not detectable in muscle fibers from patients with hereditary or sporadic disease but was expressed abundantly in muscle macrophages. In all control and inclusion body myositis or myopathy biopsy specimens, ApoE immunoreactivity was strong at the postsynaptic domain of neuromuscular junctions; nonjunctional regions of normal fibers were negative for ApoE. ApoE immunoreactivity occurred diffusely in regenerating muscle fibers, a subset of which had detectable ApoE messenger RNA.

Amyotrophic Lateral Sclerosis↗
PubMed1980

Ultrastructural classification of paracrystalline inclusions in untreated and estrogen treated human Leydig cells.

Ultrastructural examination of untreated and estrogen-treated human testes revealed for the first time five types of paracrystalline inclusions in the cytoplasm of Leydig cells. The distinctions between each type of inclusion were based on longitudinal and cross-sectional ultrastructure. The inclusions were not found in Leydig cells containing Reinke crystals, nor were different types of inclusions found in the cytoplasm of the same cell. One form of inclusion or Reinke crystals were occasionally found in the nucleus. Some Leydig cells with intranuclear inclusions contained the same or a different type of inclusion in the cytoplasm. The present study revealed five types of paracrystalline inclusion in contrast to the one or two types described in previous reports. A possible explanation for this difference is that earlier investigators based their observations on small pieces of tissue obtained from biopsy, while the present data were obtained by studying many regions of each testis. All five types of paracrystalline inclusions were found in relatively normal as well as azoospermic (estrogen-treated) testes.

Adult↗
PubMed1992

Argentophilic intracytoplasmic inclusions in multiple system atrophy.

Argentophilic intracytoplasmic glial inclusions were recently reported in olivo-ponto-cerebellar atrophy (OPCA). We examined the brains of 3 cases of OPCA [2 with striato-nigral degeneration (SND) and 1 without SND], 1 case of pure autonomic failure (PAF) without pathology of OPCA or SND, as well as 36 controls including 2 cases of Holmes' type cerebellar cortical atrophy and 2 cases of Joseph's disease. Although the inclusions were tubulin-positive, the immunoreactivity was different from that of the dendrites. Electron microscopically, the microtubular structures composing the inclusion were fuzzy with granular material. These findings may indicate that the microtubules composing the inclusions are modified. Inclusion-bearing cells appeared to be oligodendrocytes while many of them had larger and lighter nuclei than those of normal-looking oligodendrocytes without the inclusions. The inclusions were widely distributed in a characteristic fashion beyond the typical lesions of OPCA, SND and PAF. The distribution pattern was essentially the same in the case of PAF and 3 cases of OPCA irrespective of the presence or absence of OPCA or SND lesions. In contrast, argentophilic inclusions were not observed in other types of spinocerebellar degeneration, in Holmes' type cerebellar cortical atrophy or in Joseph's disease. It is suggested, in line with other studies, that the inclusion may be specific to OPCA and related disorders which include PAF and a useful marker to distinguish OPCA from other neurodegenerative diseases.

Adult↗
PubMed2004

Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study.

Ubiquitin-positive tau-negative inclusions were initially described in the rare form of frontotemporal dementia (FTD) associated with motor neuron disease. However, recent studies have indicated that these inclusions are also present in typical FTD, which is usually characterized by nonspecific histological changes. To examine the contribution of these inclusions to neuronal loss and to explore their relationship with disease duration, we performed a quantitative immunocytochemical analysis of 38 typical FTD cases. Relationships between neuron and ubiquitin inclusion densities as well as between duration of illness and neuropathological parameters was studied using linear regression in both univariate and multivariate models. Ubiquitin-positive tau-negative intracytoplasmic inclusions were present in 65.8% of cases in the dentate gyrus, 57.9% in temporal cortex and 31.6% in frontal cortex. The highest densities of ubiquitin-positive inclusions were consistently observed in the dentate gyrus, followed by the temporal and frontal cortex. There was no statistically significant relationship between neuron and ubiquitin-positive inclusion densities in any of the areas studied. In contrast, ubiquitin-positive inclusion densities in the dentate gyrus were negatively related to the duration of illness. Our data suggest that the development of ubiquitin-related pathology is the rule and not the exception in typical FTD, yet is not causally related to neuronal loss. They also reveal that the development of ubiquitin-positive inclusion densities in the dentate gyrus may be associated with a more aggressive form of the disease.

Adult↗
PubMed1999

Immunohistochemical and electron microscopical studies of myocardial inclusions in hereditary myopathy of the diaphragmatic muscles in Holstein-Friesian cattle.

In hereditary myopathy of the diaphragmatic muscles in Holstein-Friesian cattle, the largest number of acidophilic intracytoplasmic inclusions was found in the myocardium. These inclusions, which were oval and measured 12-15 microm in the transverse sections, were characterized by a dense, amorphous zone, and a relatively hyalinized sarcous substance in paraffin-embedded hematoxylin and eosin (H & E)-stained sections. Histochemically, each inclusion was stained intense red and dark green with H & E and Gomori's trichrome, respectively. NADH-TR activity was absent. The region surrounding the inclusions was less acidophilic with H & E, and showed an increased activity with NADH-TR. The inclusions showed no immunoreactivity for desmin, vimentin, actin or alpha-actinin, while strong desmin immunoreactivity was observed in the region surrounding the inclusion. Some inclusions showed strong immunoreactivity for ubiquitin, but others reacted only faintly. Ultrastructurally, the inclusion had a dense core composed of myofibrillar aggregations. The periphery of this dense core was surrounded by thin or intermediate-sized filaments, which corresponded to the desmin-positive area. This alteration was sometimes found to be continuous with the Z disk, which showed streaming or disintegration or with the desmosome of the intercalated disk. We discuss here the similarity between this specific inclusion and the other alternative organelles that have been reported previously in cardiomyopathy or in cardiac lesions associated with various myopathies.

Actins↗
PubMed2006

Affinity binding of inclusion bodies on supermacroporous monolithic cryogels using labeling with specific antibodies.

A new chromatographic method based on affinity supermacroporous monolithic cryogels is developed for binding and analyzing inclusion bodies during fermentation. The work demonstrated that it is possible to bind specific IgG and IgY antibodies to the 15 and 17 amino acids at the terminus ends of a 33 kDa target protein aggregated as inclusion bodies. The antibody treated inclusion bodies from lysed fermentation broth can be specifically retained in protein A and pseudo-biospecific ligand sulfamethazine modified supermacroporous cryogels. The degree of binding of IgG and IgY treated inclusion bodies to the Protein A and sulfamethazine gels are investigated, as well as the influence of pH on the sulfamethazine ligand. Optimum binding of 78 and 72% was observed on both protein A and sulfamethazine modified cryogel columns, respectively, using IgG labeling of the inclusion bodies. The antibody treated inclusion bodies pass through unretained in the sulfamethazine supermacroporous gel at pH that does not favour the binding between the ligand on the gel and the antibodies on the surface of inclusion bodies. Also the unlabeled inclusion bodies went through the gel unretained, showing no non-specific binding or trapping within the gel. These findings may very well be the foundation for the building of a powerful analytical tool during fermentation of inclusion bodies as well as a convenient way to purify them from fermentation broth. These results also support our earlier findings [Kumar, A., Plieva, F.M., Galaev, I.Yu., Mattiasson, B., 2003. Affinity fractionation of lymphocytes using a monolithic cyogel. J. Immunol. Methods 283, 185-194] with mammalian cells that were surface labeled with specific antibodies and recognized on protein A supermacroporous gels. A general binding and separation system can be established on antibody binding cryogel affinity matrices.

Antibodies↗
PubMed2003

Dorfin localizes to the ubiquitylated inclusions in Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis.

In many neurodegenerative diseases, the cytopathological hallmark is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. Lewy bodies in Parkinson's disease and dementia with Lewy bodies disease, glial cell inclusions in multiple system atrophy, and hyaline inclusions in amyotrophic lateral sclerosis (ALS) are representative of these inclusions. The elucidation of the components of these inclusions and the mechanisms underlying inclusion formation is important in uncovering the pathogenesis of these disorders. We hypothesized that Dorfin, a perinuclearly located E3 ubiquitin ligase, participates in the formation of ubiquitylated inclusions in a wide range of neurodegenerative diseases. Here, we report that affinity-purified anti-Dorfin antibody labeled ubiquitylated inclusions of Parkinson's disease, dementia with Lewy bodies disease, multiple system atrophy, and sporadic and familial ALS. A double-immunofluorescence study revealed that Dorfin shows a distribution pattern parallel to that of ubiquitin. Furthermore, by a filter trap assay, we detected that Dorfin is present in the ubiquitylated high-molecular weight structures derived from these diseases. These results suggest that Dorfin plays a crucial role in the formation of ubiquitylated inclusions of alpha-synucleinopathy and ALS. However, because we failed to show the direct binding of alpha-synuclein with Dorfin, future investigations into the binding partner(s) of Dorfin will be needed to deepen our understanding of the pathophysiology of alpha-synucleinopathy and ALS.

Aged↗
PubMed1998

Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of nuclear inclusions of spinal and bulbar muscular atrophy. Nuclear inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar nuclear inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural inclusions. These findings indicate that nuclear inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural nuclear inclusions.

Aged↗
PubMed2000

Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation.

The significance of neuronal intranuclear inclusions (NIIs) and extranuclear inclusions (ENNIs) in the brains of patients with polyglutamine repeat diseases and transgenic mice modelling these diseases is hotly debated. We examined inclusions in the brains of mice transgenic for the human Huntington's disease mutation and found that their size, number and location varied markedly with age and neuronal phenotype. In striatum and hippocampus particularly, inclusions appeared at different times in different cell types. Further, the mechanism of formation of inclusions appears to be complex, with several distinct phases. These include a precipitous formation of NIIs followed by NII growth, and the concomitant formation ENNIs. While the timing of appearance of NIIs and ENNIs parallels the cognitive and motor decline of the mice, the precise role of NIIs and ENNIs is unknown. It has been variously suggested that NIIs may be deleterious, benign or beneficial. However, our data allows the possibility that each of these is possible, and suggest also that the role of inclusions changes with time. The precipitous formation of NIIs may play a protective role by removing polyglutamine, while the subsequent growth of NIIs may be deleterious, since it would allow other proteins to be sequestered into inclusions. The formation of ENNIs in neurites and synapses is also more likely to have deleterious than beneficial consequences for a cell. Thus, our study suggests that the relationship between inclusion formation and neurological dysfunction depends not only upon the phenotype of the neurons involved, but also upon the molecular composition and the subcellular localisation of the inclusions.

Aging↗