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PubMedDate not supplied

Chemical pathology of homocysteine. II. Carcinogenesis and homocysteine thiolactone metabolism.

Abnormalities of methionine metabolism in malignancy include carcinogenicity of methionine deficiency, methionine auxotrophy of cultured malignant cells, deficient methylation of DNA, and aerobic glycolysis that is reversed by methionine. Cells from children with homocystinuria form an aggregated sulfated extracellular matrix and grow in a pattern similar to cultured malignant cells. Normal cells metabolize homocysteine thiolactone to sulfate, but malignant cells accumulate homocysteine thiolactone, which thiolates proteins and other cellular macromolecules. Thioretinamide, the amide of retinoic acid homocysteine thiolactone, and its cobalamin complex, thioretinaco, are antineoplastic and chemopreventive against carcinogenesis. Deficiency of these compounds in malignant cells is believed to increase conversion of methionine to homocysteine thiolactone and thioco, its cobalamin complex. These compounds are believed to participate in oxidative phosphorylation by formation of thioretinaco ozonide disulfonium complexes that are the active sites of adenosine triphosphate (ATP) binding in mitochondrial membranes. Hypothetical deficiency of thioretinaco may explain important metabolic abnormalities of malignant cells.

Anticarcinogenic Agents↗

PubMed2004

Alpha-synuclein aggregation.

Alpha-synuclein is a major component of Lewy bodies in Parkinson's disease and is found associated with several other forms of dementia. As with other neurodegenerative diseases, the ability of alpha-synuclein to aggregate and form fibrillar deposits seems central to its pathology. We have defined a sequence within the NAC region of alpha-synuclein that is necessary for aggregation. Exploitation of chemically modified analogues of this peptide may produce inhibitors of aggregation.

Amino Acid Sequence↗

PubMed2006

Biochemical and pathological characterization of Lrrk2.

OBJECTIVE: Mutations in leucine-rich repeat kinase 2 (LRRK2) recently have been identified as the most common genetic cause of late-onset sporadic and familial Parkinson's disease (PD). The studies herein explore the biological and pathological properties of Lrrk2. METHODS: Genetic analysis was performed to identify autopsied patients with the most common Lrrk2 mutation (G2019S). Using an antibody specific to Lrrk2, the biochemical and immunocytochemical distribution of Lrrk2 was assessed. RESULTS: Three patients with the G2019S Lrrk2 mutation were identified. Two patients demonstrated classic PD with Lewy bodies, although concurrent pathological changes consistent with Alzheimer's disease were also present in one of these individuals. The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2. Lrrk2 accumulations were unique to this patient and Lrrk2 was not detected in other types of pathological inclusions. Biochemical analysis showed that Lrrk2 is predominantly a soluble approximately 250 kDa cytoplasmic protein expressed throughout the brain but also in many other organs. INTERPRETATION: The reasons for the selective predisposition of patients with mutations in LRRK2 to develop parkinsonism remains unclear, but Lrrk2 mutations may prime select neuronal populations to cellular insults that can lead to aberrant protein aggregation.

Adult↗

PubMed2003

Intracellular changes in astrocytes and NG 108-15 neuroblastoma X glioma cells induced by advanced glycation end products.

INTRODUCTION: The extracellular effects caused by advanced glycation end products (AGEs) themselves formed by the Maillard-reaction from proteins and sugars, are well known. Less is known about the effects of AGEs on cellular function. Cellular dysfunctions accumulate with increasing age and can be found as a pathogenetic principle of different diseases where AGEs are involved. The causal mechanisms of these cellular dysfunctions are not fully understood. MATERIAL AND METHODS: AGEs effects were examined in cell culture using video microscopy, immunohistochemistry, flow cytometry and biochemical methods in neural (NG 108-15) and glial (primary culture of astrocytes) cells. RESULTS: AGEs can bind to the cell surface of neural and glial cells. AGEs induce an altered distribution of vesicles and a statistically significant reduction in the velocity of microvesicles. The proteins dynamin 2 and clathrin, which are an important part of the transport apparatus, show changes in intracellular distribution similar to that of microvesicles. The immunoreactivity of dynamin 2 in AGE-treated cells is increased after AGE-incubation. After incubation durations of 2 h, 6 h and 12 h we found an increase (maximum +34.6%) of the relative fluorescence intensities of dynamin 2 in the AGE-BSA treated cells in comparison to the control cells (BSA). Using flow cytometry we found a minimal increase (14.4%) in clathrin immunoreactivity after 2 h incubation with 500 nM AGE-BSA. The non-quantitative western blot showed no difference of the electrophoretic behaviour of both dynamin 2 and clathrin in AGE-BSA-incubated cells (2 h, 500 nM) and in control cells (2 h, 500 nM BSA-incubation). The incubation with AGE-BSA up to a concentration of 500 nM in culture was not followed by apoptotic or necrotic cell death. DISCUSSION: We could show defined effects on the cells induced by incubation with AGEs. One of the effects is a significant reduction of the velocity of microvesicles, the reason for this is unclear. It could be due to disturbed calcium metabolism or caused by microtubuli-changes. The aggregation of intracellular microvesicles could be the result of an altered binding-behaviour of the vesicles or the destruction of the transport apparatus. The proteins dynamin 2 and clathrin, which are involved in transport apparatus, show changes in intracellular distribution indicating a breakdown of the normal cellular distribution system. The current results may contribute to the understanding of the pathologic processes in the cell in Mb. Alzheimer and other neurodegenerative diseases, where AGEs-accumulation can be found in tissues.

Animals↗

PubMed1998

Tau in Alzheimer's disease.

Neurofibrillar protein aggregates containing tau are one of the major hallmarks of Alzheimer's disease (AD). In normal cells, tau stabilizes axonal microtubules, which are the tracks for intracellular traffic. In AD, tau becomes abnormally phosphorylated, aggregates into paired helical filaments and loses its ability to maintain the microtubule tracks. There is renewed interest in tau as a causative factor in neurodegenerative disease based on recently discovered mutations in the gene encoding tau. This article discusses how changes in tau protein could lead to retraction of neuronal processes and thus cell death and argues that tau pathology, rather than beta-amyloid, might be the most reliable indicative factor for AD.

Alzheimer Disease↗

PubMed2006

Sp1 is up-regulated in cellular and transgenic models of Huntington disease, and its reduction is neuroprotective.

Interactions between mutant huntingtin (Htt) and a variety of transcription factors including specificity proteins (Sp) have been suggested as a central mechanism in Huntington disease (HD). However, the transcriptional activity induced by Htt in neurons that triggers neuronal death has yet to be fully elucidated. In the current study, we characterized the relationship of Sp1 to Htt protein aggregation and neuronal cell death. We found increased levels of Sp1 in neuronal-like PC12 cells expressing mutant Htt, primary striatal neurons, and brain tissue of HD transgenic mice. Sp1 levels were also elevated when 3-nitropropionate (3-NP) was used to induce cell death in PC12 cells. To assess the effects of knocking down Sp1 in HD pathology, we used Sp1 siRNA, a heterozygous Sp1 knock-out mouse, and mithramycin A, a DNA-intercalating agent that inhibits Sp1 function. The three approaches consistently yielded reduced levels of Sp1 which ameliorated toxicity caused by either mutant Htt or 3-NP. In addition, when HD mice were crossed with Sp1 heterozygous knock-out mice, the resulting offspring did not experience the loss of dopamine D2 receptor mRNA characteristic of HD mice, and survived longer than their HD counterparts. Our data suggest that enhancement of transcription factor Sp1 contributes to the pathology of HD and demonstrates that its suppression is beneficial.

Animals↗

PubMed2004

Alpha-synuclein and Parkinson's disease.

Alpha-synuclein (alpha-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system. Interest in alpha-syn has increased dramatically after the discovery of a relationship between its dysfunction and several neurodegenerative diseases, including Parkinson's disease (PD). The physiological functions of alpha-syn remain to be fully defined, although recent data suggest a role in regulating membrane stability and neuronal plasticity. Various trigger factors, either environmental or genetic, can lead to a cascade of events involving misfolding or loss of normal function of alpha-syn. In dopaminergic neurons, this may promote a vicious cycle in which elevation in cytoplasmic dopamine, oxidative stress, alpha-syn dysfunction, and disruption of vesicle function lead to dopaminergic cell loss and PD. Alpha-syn dysfunction appears to be a common feature of all forms of PD. The mechanism by which alpha-syn induces neuronal cell toxicity may invoke multiple pathways, such as aggregation or interaction with other proteins and molecules, including synphilin-1, chaperone 14-3-3 protein, and dopamine itself. This complexity has hindered the development of models to study PD. The available animal models of PD, each present distinct advantages and limits. Findings to date suggest that alpha-syn-based models represent a paradigm, which is closest to the human pathology.

Amino Acid Sequence↗

PubMedDate not supplied

Optimal assay conditions for quantifying fibronectin in saliva.

INTRODUCTION: Fibronectin (Fn) is a glycoprotein that is present in many body fluids and tissues in both physiological and pathological conditions. It can also be detected in the saliva, although only in very small quantities and frequently in broken chains. It induces bacterial aggregation and its levels fall when those of cariogenic or periodontal pathogenic bacteria rise. The infective capacity of the saliva of patients infected by human immunodeficiency virus (HIV) has been linked to the levels of this protein. In some chronic conditions of the oral mucosa,such as oral lichen planus, the concentration of salivary fibronectin is lower than usual. Fibronectin quantity also varies in the presence of some tumours, such as oral squamous cell carcinoma, although it cannot be considered a specific factor. AIMS: Due to the low Fn concentration in saliva and its lability in the soluble form, sample collection and conservation conditions are extremely important. The aim of this study is therefore to standardise these conditions so that the Fn can be quantified in an optimum manner. MATERIALS AND METHODS: The Fn concentration in human saliva was determined in 20 healthy subjects aged between 28 and 54 by means of the ELISA technique and the concentration of the protein in fresh samples kept at 4 grades C for 24 hours was compared with that of frozen samples kept at 40 grades C below 0, for different periods of time. RESULTS AND CONCLUSIONS: After comparing different ways of conserving the saliva samples, we found that the optimum conditions were to collect the samples in glass tubes and to quantify them immediately after collection or conserve them at 4 grades C and quantify them within a maximum of 24 hours. Freezing and later thawing for quantification induced losses of up to 60% of the protein.

Adult↗

PubMed1994

Localization and characterization of an alpha-thrombin-binding site on platelet glycoprotein Ib alpha.

Glycoprotein (GP) Ib alpha is required for expression of the highest affinity alpha-thrombin-binding site on platelets, possibly contributing to platelet activation through a pathway involving cleavage of a specific receptor. This function may be important for the initiation of hemostasis and may also play a role in the development of pathological vascular occlusion. We have now identified a discrete sequence in the extracytoplasmic domain of GP Ib alpha, including residues 271-284 of the mature protein, which appears to be part of the high affinity alpha-thrombin-binding site. Synthetic peptidyl mimetics of this sequence inhibit alpha-thrombin binding to GP Ib as well as platelet activation and aggregation induced by subnanomolar concentrations of the agonist; they also inhibit alpha-thrombin binding to purified glycocalicin, the isolated extracytoplasmic portion of GP Ib alpha. The inhibitory peptides interfere with the clotting of fibrinogen by alpha-thrombin but not with the amidolytic activity of the enzyme on a small synthetic substrate, a finding compatible with the concept that the identified GP Ib alpha sequence interacts with the anion-binding exosite of alpha-thrombin but not with its active proteolytic site. The crucial structural elements of this sequence necessary for thrombin binding appear to be a cluster of negatively charged residues as well as three tyrosine residues that, in the native protein, may be sulfated. GP Ib alpha has no significant overall sequence homology with the thrombin inhibitor, hirudin, nor with the specific thrombin receptor on platelets; all three molecules, however, possess a distinct region rich in negatively charged residues that appear to be involved in thrombin binding. This may represent a case of convergent evolution of unrelated proteins for high affinity interaction with the same ligand.

Adenosine Triphosphate↗

PubMed1996

Inhibitors of stone formation.

Urine contains substances that inhibit the nucleation, growth, aggregation, and cell attachment of crystals. These may function to protect the kidney against the possibility of pathological calcification in tubular fluid and urine, which are generally supersaturated with respect to calcium salts, thereby preventing stone formation. Effects on calcium oxalate are the best studied, and most of the inhibitory activity resides in macromolecules such as glycoproteins and glycosaminoglycans. Inhibitory proteins found in urine include nephrocalcin, Tamm-Horsfall protein, uropontin, crystal matrix protein (F1 prothrombin fragment), and uronic acid-rich protein (bikunin). Most of the molecules are anionic, with many acidic amino acid residues, frequently contain post-translational modifications such as phosphorylation and glycosylation, and appear to exert their effects by binding to calcium oxalate surface. The specific structural motifs that favor crystal binding and inhibition are not yet known. A number of the proteins are made by renal epithelial cells, whereas others gain access to the urine by glomerular filtration. In a number of cases, abnormalities of protein structure or function have been found in stone formers. It is not yet known what proportion of stone formers have an abnormality of inhibitor function.

Calcium Oxalate↗

PubMed1999

Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin.

Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1-17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.

Animals↗

PubMed1999

Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein.

Intranuclear inclusion bodies are a shared pathological feature of Huntington's disease (HD) and its transgenic mouse model. Using a panel of antibodies spanning the entire huntingtin molecule, we have investigated the pattern of immunoreactivity within the intranuclear inclusions in the frontal cortex and striatum of patients with HD. The intranuclear inclusions reacted with anti-ubiquitin and antibodies against the N-terminal portion of huntingtin (CAG53b, HP1), but not with HD1 and the 1C2 antibodies that detect the expanded polyglutamine tract nor the more C-terminal antibodies. However, the 1C2, HP1, CAG53b, and HD1 antibodies detected granular cytoplasmic deposits in cortical and striatal neurons that also contained intranuclear N-terminal huntingtin immunoreactivity. These data show a differential intracellular location of truncated huntingtin in the HD brain. Both the cytoplasmic and the nuclear aggregates of the protein fragments could be neurotoxic. The frequency of the cortical intranuclear inclusions correlated with the size of CAG expansion and was inversely related to the age at onset and death. No such correlations were detected for the striatum, which most likely reflects a more advanced neuronal loss accrued by the time of death.

Adult↗

PubMed2026

TRIM21 induces selective autophagy of viruses and bacteria.

TRIM21 is an exceptionally versatile ubiquitin ligase that can be directed by antibodies to target oligomeric protein scaffolds, viral capsids, and proteopathic aggregates for intracellular degradation. How the cell degrades these typically resistant substrates remains poorly understood. To address this, we used TRIM21 viral restriction to create a genome-wide phenotypic screen for antibody-dependent capsid degradation. We identify an antimicrobial selective macroautophagy pathway in mammalian cells, which we term "antibody-directed xenophagy" (ADX). We show that this mechanism restricts structurally diverse pathogens, including adenovirus and Salmonella. Using quantitative microscopy, we demonstrate that TRIM21 rapidly intercepts antibody-pathogen complexes, leading to ubiquitin ligase activation. Following this, selective autophagy adaptors are recruited, and viral cargoes are delivered to lysosomes. This process reduces Salmonella pathology and bacterial tissue invasion in mice. We propose that TRIM21 evolved through competition with pathogens to induce autophagy of diverse and complex substrates, potentially explaining its versatility for targeted protein degradation.

TRIM21 Protein↗

PubMed1994

Reciprocal interactions between human ovarian surface epithelial cells and adjacent extracellular matrix.

The human ovarian surface epithelium (OSE), or ovarian mesothelium, is functionally complex as seen by its capacity to proliferate, migrate, and contribute to ovulation and ovulatory repair in response to cyclic hormonal and environmental changes. We wished to determine whether this phenotypic versatility is reflected in cell-extracellular matrix interactions in primary and low-passage culture. Comparisons of cultures maintained on different substrata revealed that these cells form cohesive monolayers on plastic, while fibrin clots enhance cell dispersion, and thus may provide a migratory cue. The cells invaded Matrigel as multicellular aggregates, while collagen gels mediated a morphologic epithelial-mesenchymal conversion. On plastic, the cells produced extracellular matrix components characteristic of epithelial basement membrane (laminin and collagen type IV), as well as stroma (collagen types I and III). In addition, ovarian surface epithelial cells secreted serine proteases and matrix metalloproteinases. The levels of chymotrypsin- and elastase-like proteases were dictated by the substratum: low levels were secreted by cells grown on plastic, intermediate levels on collagen gels and fibrin clots, and most protease was produced on Matrigel. The rate of cell proliferation varied with the substrata and was inversely related to protease secretion. Integrin expression was greatest on plastic and least on collagen gels where integrins were downregulated with time. alpha 6/beta 4 was absent from all cells while varying levels of alpha 2, alpha 3, alpha 5, beta 1, and vitronectin receptor were detected depending on the culture substratum employed. In low-passage cultures of human ovarian surface epithelial cells, then, cell shape, growth, protease production, and integrin expression are modulated by the extracellular matrix. The cells, in turn, alter extracellular matrix by synthesis, lysis, and physical remodeling, and express both stromal and epithelial characteristics. The broad repertoire of these functions may be related to their mesodermal origin, and may reflect the expression of a dual, epithelio-mesenchymal phenotype by relatively immature, uncommitted cells. The results demonstrate the great complexity and versatility of these interactions which render OSE cells capable of participating in numerous physiological and pathological processes.

Adult↗

PubMed1981

Homozygous haemoglobin Constant Spring: a need for revision of concept.

Twenty-two patients with mild haemolytic anaemia and haemoglobin (Hb) Constant Spring (CS) of around 6% were studied because they were suspected of having homozygous Hb CS. Family studies revealed Hb CS trait in both parents of eight patients, supporting that they were homozygous for Hb CS. The other patients were included because they had clinical and haematological features similar to the diagnosed cases of homozygous Hb CS. Heterozygosity and homozygosity for Hb CS are clearly distinguishable in that the former is asymptomatic but the latter is associated with overt haemolytic anaemia, and the levels of Hb CS in the two conditions of less than 1% and around 6%, respectively, do not overlap. The findings in homozygous Hb CS contradict prediction. There are four alpha-structural genes per normal human diploid genome. Hb CS trait is believed to be almost equivalent to alpha-thalassaemia 2 or a loss of one alpha-gene because HB CS, and alpha-variant, is barely or not detectable. Homozygosity for Hb CS has thus been predicted to be equivalent to alpha-thalassaemia 1 or a loss of two genes. The latter is asymptomatic and associated with microcytic-hypochromic red cells. However, Hb CS homozygosity presents with mild overt haemolytic anaemia and normal sized red cells. Pathogenesis associated with Hb CS inheritance is more complex than originally believed. There is a possibility that the unstable alpha CS mRNAs precipitate and aggregate leading to pathology of red cells and to the basophilic stippling appearance, so striking in this syndrome.

Adolescent↗

PubMed1988

An overview of hemostasis.

The normal hemostatic system is complex yet exquisitely well regulated. Interrelationships exist between responses of the vasculature, circulating platelets, coagulation proteins, and fibrinolytic mechanism. These relationships serve to limit blood loss, preserve tissue perfusion, and stimulate local repair processes. Natural inhibitors of coagulation and fibrinolysis modulate these systems to prevent uncontrolled thrombosis or hemorrhage following pathologic stimuli. Vascular endothelial cells play an important role in the maintenance of a thromboresistant luminal interface with circulating cells and proteins. Normal hemostasis also requires the synthetic, metabolic, and repair processes of the vascular endothelium. The initial vascular response to injury produces brief vasoconstriction and exposes subendothelial substances that attract circulating platelets and activate coagulation proteins. Platelets respond by adherence and aggregation at the site of injury, with subsequent release of substances that mitigate blood loss. Platelet adherence to collagen requires von Willebrand's factor, fibrinogen, fibronectin, and specific glycoprotein receptors on platelet surfaces. Platelet-to-platelet interactions (aggregation) recruit additional platelets to the primary hemostatic plug. Aggregation requires fibrinogen, energy, and calcium. Release of ADP, serotonin, and the contents of intracellular granules as well as generation of prostaglandins prepares platelet surfaces for reactions with the coagulation proteins. Activation of the intrinsic or extrinsic coagulation pathway, or of both, causes formation of fibrin from fibrinogen by means of an elaborate and intricate system that also entraps platelets and activated coagulation proteins. The intrinsic system is activated by the contact of factor XII with a negatively charged surface, most likely collagen. Through a series of reactions with prekallikrein, HMWK, and factors XI, IX, and VIII, the common coagulation pathway is propagated. The extrinsic, or tissue factor, system stimulates both the common pathway and factor IX the intrinsic pathway. Discovery of this stimulation of the intrinsic pathway by factor VII in the extrinsic pathway has stimulated reassessment of the biologic importance of the extrinsic system. The common pathway includes factors X and V and causes thrombin to convert fibrinogen to fibrin. Calcium and platelet phospholipids are substances that have important roles in steps in the coagulation scheme. Once fibrin is formed, factor XIII interacts with the substance, providing a stabilizing effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

2,5-Hexanedione-induced intermediate filament aggregates contain ubiquitin-protein conjugate immunoreactivity and resemble Rosenthal fibres.

A number of chronic degenerative disorders including cerebellar astrocytomas and Parkinson's disease are characterized by the presence of cytosolic inclusions which contain intermediate filament (IF) aggregates and ubiquitin-protein conjugate immunoreactivity. In cerebellar astrocytomas these inclusions are known as Rosenthal fibres. 2,5-hexanedione (HD) treatment is known to induce IF aggregates in cells in culture. HD-induced aggregates have therefore been studied as a potential model for the clinical inclusions. Exposure of astrocyte cultures to 2 mM HD for 2 or 4 weeks led to the formation of aggregates of the IFs (glial fibrillary acidic protein and vimentin). The aggregates contained ubiquitin-protein conjugates, which, on electron microscopy appeared to be localized in a peripheral shell. In addition, ubiquitin mRNA levels were found to be elevated approximately threefold by HD treatment. HD-induced inclusions and Rosenthal fibres were found to share a number of features. HD administration, therefore, appears to be a suitable model for the production of pathological inclusions.

Animals↗

PubMedDate not supplied

Role of cdk5 in the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by two pathological hallmarks, namely, senile plaques and neurofibrillary tangles (NFTs). The former are mainly composed of amyloid-beta peptides (Abeta) while the latter consists mainly of filaments of hyperphosphorylated tau. Cyclin-dependent kinase 5 (cdk5) has been implicated not only in the tangle pathology, but recent data also implicate cdk5 in the generation of Abeta peptides. Since both Abeta peptides and NFTs are believed to play a role in neurodegeneration in AD, this proline-directed serine/threonine protein kinase is likely to contribute to the pathogenesis of AD. In vitro and in vivo animal data demonstrate the ability of cdk5 to induce phosphorylation and aggregation of tau, and NFT deposition and neurodegeneration. Findings from AD brain samples also show an elevated cdk5 activity and conditions that support the activation of cdk5. Evidence for the role of cdk5 in regulating Abeta production is just emerging. The mechanisms for this potentially damaging activity of cdk5 are largely unknown although amyloid precursor protein and presenilin-1 are both cdk5 substrates.

Alzheimer Disease↗