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M Landon

Publications and source records attributed to M Landon.

At least 73 records · Page 4Linked to original sources
PubMed1991

The role of protein ubiquitination in neurodegenerative disease.

Ubiquitin immunocytochemistry with an antiserum which reacts with ubiquitin-protein conjugates demonstrates the presence of ubiquitinated proteins in filamentous inclusions found in neurones in the major human neurodegenerative diseases, i.e. Alzheimer's disease, diffuse Lewy body disease, motor neurone disease. Ubiquitin immunohistochemistry has revolutionized the neuropathological diagnosis of dementia showing that diffuse Lewy body disease is not, as previously supposed, a rare cause of dementia. The filamentous inclusions in neurones in the human neurodegenerative diseases can be divided into at least two types based on recent immunocytochemical studies. We have shown that a ubiquitin-carboxyl terminal hydrolase is present in Lewy bodies but not in neurofibrillary tangles in Alzheimer's disease. This observation is significant since it indicates that molecular pathological mechanisms in neurones in diffuse Lewy body disease are fundamentally different to Alzheimer's disease. Ubiquitin-protein conjugates are also found in vacuoles in areas of granulovacuolar degeneration in hippocampal neurones in Alzheimer's disease and in granulovacuoles in neurones of scrapie infected mouse brain. These locations suggest that ubiquitinated protein are present in the lysosome-related system of neurones. We have recently shown that ubiquitin-protein conjugates are indeed enriched some 12-fold in the lysosomes of normal fibroblasts and lymphocytes.

Brain Diseases↗
PubMed1990

Ubiquitin carboxyl-terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases.

The recent discovery that brain PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase suggests that the role of this protein should be studied in relation to ubiquitinated cellular inclusions characteristic of several chronic human degenerative diseases. Formalin-fixed, paraffin-processed sections known to contain ubiquitin-protein conjugate immunoreactivity in cortical Lewy bodies, neurofibrillary tangles, Rosenthal fibres, Pick bodies, spinal inclusions in motor neurone disease, and Mallory's hyaline in alcoholic liver disease were immunostained to localize PGP 9.5. The majority of cortical Lewy bodies in diffuse Lewy body disease showed immunoreactivity for PGP 9.5. In Alzheimer's disease, only a minority of loosely arranged globose-type neurofibrillary tangles were immunostained together with a minority of neurites surrounding senile plaques. In cerebellar astrocytomas, the periphery of the majority of Rosenthal fibers was immunostained in addition to strong diffuse cytoplasmic immunostaining in some astrocytes lacking apparent Rosenthal fibers. In Pick's disease, there was no immunostaining of inclusions but there was intense immunostaining of swollen Pick cells. No spinal inclusions in motor neurone disease were stained; however, anterior horn neurones appear to show increased levels of PGP 9.5 compared with those from control cases. No immunostaining of hepatic Mallory's hyaline was demonstrable, which accords with suggestions that PGP 9.5 is a tissue-specific ubiquitin C-terminal hydrolase isoenzyme. The differential detection of a ubiquitin C-terminal hydrolase in different forms of ubiquitinated inclusion body in the nervous system may form the basis of a method for assessment of the staging of inclusion body biogenesis and give insight into the dynamics of inclusion body formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗
PubMed1990

Ubiquitin conjugate immunoreactivity in the brains of scrapie infected mice.

Sections of brain from normal mice or clinically-ill mice infected with either the 87V or the ME7 strains of sheep scrapie were immunostained to show the localization of ubiquitin-protein conjugates or a specific marker of disease, the scrapie-associated fibril protein (PrP). In both scrapie models immunoreactive ubiquitin-protein conjugates were seen in thread-like structures found throughout the neuropil, in inclusion bodies within vacuolated neurones, and in areas surrounding anti-PrP positive amyloid plaques. The PrP protein was visualized in diffuse deposits in highly vacuolated parts of the scrapie-affected brain, and focally in amyloid plaques, microglia and neuronal processes. The ubiquitin-protein conjugate staining of scrapie amyloid plaques is very similar to that seen in the plaques of Alzheimer's disease. The ubiquitinated intraneuronal inclusion bodies seen in scrapie resemble the granulovacuolar lesions also seen in Alzheimer's disease, but appear much larger and possibly correspond to material in giant autophagic vacuoles. We suggest that these inclusions may be the result of ubiquitinated abnormal proteins being directed to the lysosomal system, and that scrapie and Alzheimer's disease share at least some common processes of neurodegeneration.

Amyloid↗
PubMed1990

Distinction of NPY receptors in vitro and in vivo. II. Differential effects of NPY and NPY-(18-36).

We have studied the hemodynamic effects of neuropeptide Y (NPY) and its COOH-terminal fragment NPY-(18-36) in conscious rats. Intra-arterial injection of NPY rapidly elevated systemic vascular resistance (SVR), which remained high for greater than 30 min. Cardiac output (CO) decreased, and it remained low for greater than 30 min. Accordingly, blood pressure rose only transiently and returned to base-line values within 5 min. The reduction of CO could be attributed to a decreased stroke volume with an only marginal reduction of heart rate. Thus a direct cardiodepressive effect of NPY rather than baroreflex activation appears to be the major cause of the reduced CO. In vitro experiments excluded the possibility that NPY has direct negative inotropic effects and suggest that its cardiodepressive action is caused by coronary vasoconstriction or by presynaptic inhibition of norepinephrine release. Intra-arterial injections of NPY-(18-36) caused different hemodynamic effects. NPY-(18-36) decreased CO in a manner similar to that seen with NPY but initially did not elevate SVR, resulting overall in a reduced blood pressure. Only later, when blood pressure was reduced, was an elevation of SVR observed, which could be associated with increased plasma levels of catecholamines, angiotensin II, vasopressin, and NPY. Thus NPY-(18-36) mimics the cardiac effects of NPY but does not elicit its vascular effects. As NPY-(18-36) discriminates between NPY receptor subtypes in vitro, we conclude that the cardiac and vascular effects of NPY are mediated by distinct receptor subtypes.

Animals↗
PubMed1990

Measurement of cervical length in pregnancy: comparison between vaginal ultrasonography and digital examination.

Evaluation of the gravid cervix uteri is an important part of prenatal care, especially in the patient at risk for preterm birth. Seeking a method of cervical length measurement that could be used easily regardless of patient habitus, location of the cervix, and gestational age, we used a vaginal probe with a 240 degrees scanning angle in gravidas at various gestational ages to test the theoretical advantages of the wide scanning angle. Among the first 201 examinations, cervical length was measured successfully in 99.5% of cases. This success rate compares favorably with those of abdominal sonography and vaginal sonography using the standard 90 degrees scanning angle sector probes. We also compared this method with digital examination in a double-blind fashion. Only a fair degree of association between sonographic cervical measurements and measurements obtained by digital examination was found, reflected in a correlation coefficient of 0.49.

Cervix Uteri↗
PubMed1989

Inclusion bodies in motor cortex and brainstem of patients with motor neurone disease are detected by immunocytochemical localisation of ubiquitin.

Histological sections of cerebral motor cortex, brainstem, and spinal cord from 10 cases of clinically diagnosed motor neurone disease (MND) and 10 control cases were examined by conventional histology and immunocytochemical methods to localise ubiquitin. Intracytoplasmic inclusion bodies were identified in motor neurones of hypoglossal nuclei and appeared specific for MND. Similar inclusions were found in both large pyramidal cells and small neurones in the motor cortex, and were restricted to 4 cases having the amyotrophic lateral sclerosis form of MND with severe degeneration of corticospinal tracts. As reported in earlier studies, cellular inclusion bodies were identified in motor neurones of spinal cord from cases of MND but not in control material. Ubiquitin inclusions in motor neurones appear to be markers for the degenerative process causing neuronal loss in MND and there appears to be a close association between the anatomical location of inclusions and clinical manifestations of disease.

Aged↗
PubMed1989

Ubiquitin gene expression in brain and spinal cord in motor neurone disease.

A restriction fragment of the coding region of a human ubiquitin gene has been used in Northern analyses of RNA prepared from human motor cortex and anterior horn region of cervical spinal cord. The analyses show that there is a substantial increase (approximately two-fold) in the expression of a polyubiquitin gene in motor cortex and spinal cord from patients with motor neurone disease compared to these tissues from control cases. Polyubiquitin gene expression in other organisms is associated with physical or chemical cell stresses. The data indicate that the primary stresses which result in the generation of ubiquitinated filamentous inclusion bodies in neurones in motor neurone disease also result in increased transcription of a gene coding for a polyprotein of ubiquitin.

Adult↗
PubMed1989

Immunocytochemical profile of neurofibrillary tangles in Down's syndrome patients of different ages.

Brains were obtained at autopsy from 24 patients with Down's syndrome, ranging in age from 13 to 71 years. Neurofibrillary tangle containing neurones of the hippocampus were stained using a Palmgren silver method and immunocytochemically (PAP) using antisera to paired helical filament protein, human tau protein and ubiquitin, as primary antibody. Counts of cells stained by each method were compared. In patients under 50 years of age, in whom only a limited number of tangle bearing cells were present, the number of profiles visualized with silver, anti-paired helical filament and anti-tau methods were similar. However, in patients over 50 years of age (and in certain of those under 50), in whom numerous tangles were present, the number of cell profiles visualized with silver and anti-paired helical filament methods were still similar though anti-tau detected fewer positive cells. This was because of the increased presence, in such patients, of extracellular tangles which had "lost" anti-tau immunoreactivity. Such data suggest that although tau protein forms a major antigenic determinant of neurofibrillary tangles in Down's syndrome (as it does in Alzheimer's disease) this protein may only decorate the basic paired helical filament protein skeleton, and is removed by macrophagic activity upon neuronal death. In all patients, anti-ubiquitin revealed fewer tangles than any other method. It is possible that ubiquitin may be present only transiently, within tangles perhaps following initial formation and lasting only as long as the normal protein degradation processes remain viable within the diseased neurone.

Adolescent↗
PubMed1989

Anti-ubiquitin immunocytochemistry is more sensitive than conventional techniques in the detection of diffuse Lewy body disease.

Brainstem and cortical Lewy bodies in diffuse Lewy body disease show intense immunoreactivity to antibodies against ubiquitin. Quantitative studies show that the novel neuropathological technique of anti-ubiquitin immunocytochemistry is more than twice as sensitive as conventional haematoxylin and eosin stains in detecting cortical Lewy bodies. Anti-ubiquitin immunocytochemistry should be regarded as the method of choice for the diagnosis and quantification of diffuse Lewy body disease.

Antibodies↗
PubMed1989

Diffuse Lewy body disease: correlative neuropathology using anti-ubiquitin immunocytochemistry.

Diffuse Lewy body disease is an important pathological substrate of the common syndrome of parkinsonian dementia. The new technique of anti-ubiquitin immunocytochemistry has been used in a correlative quantitative neuropathological study of fifteen cases of diffuse Lewy body disease, showing that the severity of dementia is related to cortical Lewy body density, whilst subcortical abnormalities make a much less significant contribution. Cortical senile plaques also appear to be part of the pathology of diffuse Lewy body disease and should not therefore be used as an isolated diagnostic criterion for Alzheimer's disease. Diagnostic criteria for diffuse Lewy body disease are discussed.

Aged↗
PubMed1989

Intermediate filaments and ubiquitin: a new thread in the understanding of chronic neurodegenerative diseases.

We have recently shown that there is a previously unsuspected link between the intracellular inclusions seen in several major chronic human degenerative diseases, including neurodegenerative diseases: the inclusions showing ubiquitin immunoreactivity. The conditions include Parkinson's disease, motor neurone disease, Alzheimer's disease, Pick's disease, and alcoholic liver disease as well as cerebellar astrocytomas and a myopathy. The inclusions found in these diseases are reported to contain intermediate filaments: neurofilaments are associated with Lewy bodies in Parkinson's disease, Pick's bodies in Pick's disease and neurofibrillary tangles in Alzheimer's disease, cytokeratins are found in Mallory bodies in alcoholic liver disease, glial fibrillary acidic proteins and vimentin are found in Rosenthal fibres in astrocytomas, and desmin is found in cytoplasmic bodies in cytoplasmic body myopathy. Therefore five classes of intermediate filaments are found in inclusions which also contain ubiquitin immunoreactivity; we have also shown that ubiquitin immunoreactivity is present in vesicles in some areas of granulovacuolar degeneration in Alzheimer's disease. Protein ubiquitination is considered a signal for extralysosomal protein degradation, (although ubiquitination may have several other important functions). We have recently shown that intermediate filaments are involved in protein sequestration before degradation by lysosomally mediated autophagy: therefore intermediate filament-containing ubiquitinated inclusions may be the hallmarks of cellular attempts to eliminate pathogenic insults by the activation of both extralysosomal and lysosomal mechanisms of intracellular protein degradation. We have recently been able to reproduce, at least in part, some of the clinical observations in tissue culture cells. Ubiquitinated protein conjugates accumulate in lysosomes in fibroblasts treated with the lysosomal cysteine protease inhibitor E-64, which may mimic aspects of granulovacuolar degeneration.

Chronic Disease↗
PubMed1989

Intermediate filament-ubiquitin diseases: implications for cell sanitization.

The molecular pathology of chronic degenerative disease is not understood. Generally there must be two related, but opposing, processes: the direct deleterious effects of the pathogenic insult which can be chemical or viral and a cellular cytoprotective response to the insult. We have recently shown that there is a previously unsuspected link between the intracellular inclusions seen in some major chronic degenerative diseases: the inclusions contain ubiquitin immunoreactivity. The conditions include Parkinson's disease, motor neurone disease, Alzheimer's disease and alcoholic liver disease as well as astrocytomas and a myopathy. Protein ubiquitination is considered a signal for extra-lysosomal protein degradation although ubiquitin-protein conjugation may have several other important functions. Intermediate filaments are a component of some of the inclusions in diseased cells; we have previously reported that they are involved in protein sequestration for degradation by lysosomally mediated autophagy. Therefore, intermediate-filament-containing ubiquitinated inclusions may be hallmarks of cellular attempts to eliminate pathogenic insults by activating protein degradation mechanisms. Ubiquitinated inclusions could also be a hallmark of viral infections: they are in polio-virus-infected anterior horn neurones and Epstein-Barr-transformed lymphoblastoid cells. Some of the clinical observations can be reproduced experimentally in tissue culture cells. The implications of the combined clinical and experimental observations for cell sanitization and protein catabolism will be discussed.

Alzheimer Disease↗
PubMed1989

Ubiquitin-protein conjugates: clinical and experimental findings.

Ubiquitin has been extensively studied as a protein which is a cofactor in extralysosomal protein degradation, particularly in reticulocyte lysates. Ubiquitin is also found conjugated to nuclear histones and surface receptors in somatic cells. Until recently the occurrence of stable cellular ubiquitin-protein conjugates in physiological and pathological states had not been considered and studied. Recently we have shown that ubiquitin-protein conjugate immunoreactivity is a clinical feature in several ostensibly unrelated chronic human degenerative diseases as well as in some viral diseases. The consistent observation is the occurrence of intracellular extralysosomal inclusions containing intermediate filaments and ubiquitin conjugates as determined by immunohistochemical methods. These diseases are therefore part of a family of intermediate filament-ubiquitin diseases. The involvement of intermediate filaments with ubiquitin, a protein of known significance in protein degradation, ties in with separate evidence for a close role between intermediate filaments and protein degradation. We have previously shown that intermediate filaments may be involved in protein sequestration for degradation in the lysosomal system. Clinical immunohistochemical observations suggest that elements of the lysosomal degradation system and the ubiquitin-dependent extralysosomal system are involved in the molecular pathogenesis of some diseases. To underpin these clinical observations, we have recently shown that ubiquitin-protein conjugates accumulate in lysosome-related multivesicular bodies in cells in which lysosomal degradation is impaired. This phenomenon may result from increased ubiquitin protein-conjugate formation in cells with a compromised lysosomal system followed by chance uptake into multivesicular bodies. Alternatively, ubiquitination may normally serve as a signal for protein uptake into the lysosomal system, ubiquitinated protein-conjugates may therefore accumulate in cells with a functionally impaired lysosomal system.

Cell Compartmentation↗
PubMed1989

Immunoaffinity chromatographic purification of amyloid-related proteins from Alzheimer's disease brain tissue.

We describe the preparation and characterisation of an immunoaffinity column of immobilised monoclonal antibody 1G10/2/3 which was raised against a synthetic peptide representing residues 8-17 of the A4 amyloid protein (or beta-protein) of Alzheimer's disease (AD). In previous work we have shown that this antibody reacts in formalin-fixed, paraffin-embedded tissue sections with plaque cores, plaque periphery and cerebrovascular amyloid of AD. We have used the column in the immunoaffinity isolation from extracts prepared from AD brain tissue of a protein with an apparent molecular weight of 31,000; this protein is reactive with 1G10/2/3 in Western blots. The same protein is also present, but at lower level, in normal control brain tissue. Possible relationships of this protein to the predicted structures for full-length A4-precursors are discussed. However, in view of the preliminary nature of the observations and potential problems relating to proteolysis occurring post-mortem or during the extraction process, firm conclusions cannot be drawn about any role for this molecule in the normal functioning of A4-precursors or in the conversion of A4-precursor to the deposits of A4 seen in AD brain. Nevertheless, we conclude that we are seeing a stable but truncated form of A4-precursor and it will be of interest to see if further studies can clarify the possible relevance of the protein to normal or pathological processes in human brain tissue.

Alzheimer Disease↗