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Results for “Protein Aggregation, Pathological”

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PubMed1981

Effects of permeation of plasma proteins in diabetic patients.

A within-person trial in 35 diabetic subjects investigated the effect of six months' administration of 750 mg of calcium dobesilate daily on the erythrocyte sedimentation rate, erythrocyte and leucocyte counts, platelet aggregation, blood cholesterol and triglyceride concentrations, total serum protein concentration, electrophoretically determined serum proteins fractions, and the escape rate of intravenously injected 131-I-albumin. Significant increases in intravenous retention of 131-I-albumin, serum albumin and beta-globulin fractions, and total serum protein concentration resulted. No change in the remaining variables was detected. The results suggest that calcium dobesilate reduces pathologically increased transcapillary escape rate in diabetes mellitus.

Benzenesulfonates↗

PubMedDate not supplied

[The microtubule-associated protein tau in neurodegenerative diseases. Tauopathies].

INTRODUCTION: Microtubules are the essential components of the cytoskeleton, they are responsible for the formation and maintenance of the neuronal morphology and their specific connections. The microtubule associated proteins (MAPs) contribute to regulate the dynamism and stability of the microtubules, and therefore they are essential to maintain the correct function of the microtubules. Among them, tau is a protein that seems to be crucial in stabilizing the neuronal polarity. DEVELOPMENT: In this paper, factors affecting the affinity of tau to bind microtubules are reviewed, giving special attention to the processes that take place in the neurodegenerative diseases that present neurofibrillary tangles (NFTs), aggregates composed of modified tau in form of paired helical filaments (PHFs). One of the most important tau modification in this aberrant aggregates is the hyperphosphorylation. Thus, kinases and phosphatases responsible for tau modification could be altered in certain pathologies, leading to a decrease in the affinity of tau to bind microtubules and carrying out its self assembling and aberrant aggregation in the neurons of the affected nervous system regions. Those pathologies presenting a tau disfunction are known as tauopathies.

Alzheimer Disease↗

PubMed1993

Antiphospholipid antibodies: specificity and pathophysiology.

Antiphospholipid antibodies are autoantibodies that can be detected in plasma or serum with phospholipid-dependent coagulation tests or solid-phase immunoassays. The presence of these autoantibodies is strongly associated with an increased risk for arterial and venous thrombosis, recurrent fetal loss and thrombocytopenia. This paradoxical association of the in vitro prolongation of clotting assays and in vivo thrombosis has stimulated the search for the real antigen to which the autoantibodies are directed. A large number of potential pathological mechanisms have been proposed, and although disturbance of a certain metabolic pathway by the antibodies can explain a thrombotic tendency in one patient, no general pathological mechanism explaining thrombosis in the whole patient population has been found. This suggests that the antiphospholipid antibodies are a heterogeneous group of autoantibodies and is supported by the recent observations that antiphospholipid antibodies are not directed against phospholipids alone but against a combination of phospholipids and phospholipid-binding proteins. Both the phospholipid and the protein are part of the antigen. For the detection of antiphospholipids in an ELISA set-up, beta 2-glycoprotein I is the protein cofactor. In the coagulation tests, beta 2-glycoprotein, as well as prothrombin, can act as cofactor. However, the presence of these two proteins as a part of the epitope of the antiphospholipid antibodies does not explain the thrombotic tendency in the patient group. We have found that more physiologically relevant cofactors such as protein C and protein S, for which it is known that a partial deficiency is correlated with a thrombotic tendency, can also act as cofactors for the binding of antiphospholipid antibodies. It is concluded that antiphospholipid antibodies are a heterogeneous group of autoantibodies with varying affinity for different protein-phospholipid complexes and that inhibition of the biological activity of the protein part of the complex determines the pathological capacity of the antibodies.

Abortion, Habitual↗

PubMed2006

NF-kappaB pathway: a target for preventing beta-amyloid (Abeta)-induced neuronal damage and Abeta42 production.

Beta-amyloid (Abeta) peptides are key proteins in the pathophysiology of Alzheimer's disease (AD). While Abeta42 aggregates very rapidly to form early diffuse plaques, supplemental Abeta40 deposition is required to form mature neuritic plaques. We here investigated the role of nuclear factor-kappaB (NF-kappaB) pathway in Abeta40-mediated neuronal damage and amyloid pathology. In rat primary neurons and human postmitotic neuronal cells, the Abeta peptide induced a dose-dependent neuronal death, reduced the levels of the anti-apoptotic protein Bcl-XL, enhanced the cytosolic release of cytochrome c, and elicited the intracellular accumulation and secretion of Abeta42 oligomers. Moreover, Abeta40 activated the NF-kappaB pathway by selectively inducing the nuclear translocation of p65 and p50 subunits, and promoted an apoptotic profile of gene expression. As inhibitors of the NF-kappaB pathway, we tested the capability of a double-stranded kappaB decoy oligonucleotide, the anti-inflammatory drug aspirin and the selective IkappaB kinase 2 inhibitor, AS602868, to modify the Abeta40-mediated effects. These treatments, transiently applied before Abeta exposure, completely inhibited p50/p65 nuclear translocation and neuronal damage. The kappaB decoy also inhibited the Abeta-induced release of cytochrome c, restored the levels of Bcl-XL, and prevented intraneuronal accumulation and secretion of Abeta42. These results open up interesting perspectives on the development of novel strategies targeting out NF-kappaB p50/p65 dimers for pharmacological intervention in AD.

Amyloid beta-Peptides↗

PubMed2002

Progressive supranuclear palsy: clinical and genetic aspects.

PURPOSE OF THE REVIEW: This review focuses on the recent additions to the literature in the clinical and genetic aspects of progressive supranuclear palsy. RECENT FINDINGS: Clinical features of progressive supranuclear palsy are reasonably well established and known to be quite characteristic. Recent epidemiological studies suggest that the disorder is more common than previously considered and that it is frequently misdiagnosed. New laboratory and novel imaging techniques are being tested and cerebrospinal fluid levels of tau protein have been found helpful in diagnosis. Pathological and biochemical studies in progressive supranuclear palsy brains have shown the predominance of hyperphosphorylated tau isoforms which contain the sequence encoded by exon 10 (4R) aggregated into filaments. Familial tauopathies linked to tau gene mutations showing clinical and neuropathological overlap with sporadic progressive supranuclear palsy have been described. Despite recent discoveries of the strong genetic association of sporadic progressive supranuclear palsy with tau gene polymorphisms, a specific risk allele for developing the palsy has not yet been identified yet. SUMMARY: Recent clinical studies and clinicopathological correlations are contributing significantly to the delineation of the clinical features of progressive supranuclear palsy. These features and the appropriate use of laboratory tests allow for an earlier identification of the disease and a more accurate premortem diagnosis. However, no specific biological markers for the disorder are available yet, and consequently diagnosis in the early stages or when some of the characteristic signs and symptoms are missing, remains a major challenge. Despite the recent advances in the understanding of genetic factors involved in progressive supranuclear palsy, the cause of the disease still remains unknown. Biochemical studies in brains from progressive supranuclear palsy patients provide a potential helpful instrument to improve the characterization of this disorder.

Humans↗

PubMed2005

Free heme toxicity and its detoxification systems in human.

Severe hemolysis or myolysis occurring during pathological states, such as sickle cell disease, ischemia reperfusion, and malaria results in high levels of free heme, causing undesirable toxicity leading to organ, tissue, and cellular injury. Free heme catalyzes the oxidation, covalent cross-linking and aggregate formation of protein and its degradation to small peptides. It also catalyzes the formation of cytotoxic lipid peroxide via lipid peroxidation and damages DNA through oxidative stress. Heme being a lipophilic molecule intercalates in the membrane and impairs lipid bilayers and organelles, such as mitochondria and nuclei, and destabilizes the cytoskeleton. Heme is a potent hemolytic agent and alters the conformation of cytoskeletal protein in red cells. Free heme causes endothelial cell injury, leading to vascular inflammatory disorders and stimulates the expression of intracellular adhesion molecules. Heme acts as a pro-inflammatory molecule and heme-induced inflammation is involved in the pathology of diverse conditions; such as renal failure, arteriosclerosis, and complications after artificial blood transfusion, peritoneal endometriosis, and heart transplant failure. Heme offers severe toxic effects to kidney, liver, central nervous system and cardiac tissue. Although heme oxygenase is primarily responsible to detoxify free heme but other extra heme oxygenase systems also play a significant role to detoxify heme. A brief account of free heme toxicity and its detoxification systems along with mechanistic details are presented.

Animals↗

PubMed2000

Neurofilament-rich intraneuronal inclusions exacerbate neurodegenerative sequelae of brain trauma in NFH/LacZ transgenic mice.

Several neurodegenerative disorders are characterized by filamentous inclusions in neurons that selectively degenerate. The role these inclusions play in neuron degeneration is unclear, but this issue can be investigated experimentally in relevant animal models. The NFH/LacZ transgenic (TG) mice overexpress the high-molecular-weight neurofilament (NF) subunit (NFH) fused to beta-galactosidase, and these hybrid proteins aggregate into NF-rich, filamentous neuronal cytoplasmic inclusions (NCIs) that have been implicated in the progressive, age-dependent degeneration in subsets of affected neurons. Thus, these TG mice recapitulate some of the key pathology of neurodegenerative disorders with intraneuronal inclusions. To determine if the NCIs compromise neuron survival following traumatic brain injury (TBI), 3- to 6-month old TG and wild-type (WT) mice were subjected to TBI or sham injury. At 2 weeks post-TBI, the TG group showed increased TUNEL staining and activated caspase-3 immunoreactivity in cells of cerebral cortex, adjacent white matter, and hippocampus underlying the injury site, relative to control mice, but this labeling decreased at 4 weeks and was minimal thereafter. Compared to control mice, by 8 weeks postinjury, the TG mice showed a marked decrease in neuron density and increased gliosis in the hippocampal dentate gyrus and CA3 region as well as in the lateral thalamus, while the few remaining CA3 neurons exhibited cytoskeletal alterations, decreased synaptic protein immunoreactivity, and dissolution of NCIs. The more profound long-term neurodegenerative sequelae of TBI in the NFH/LacZ mice compared to WT mice suggest that the presence of intraneuronal inclusions may impair the recovery and long-term viability of injured neurons.

Animals↗

PubMed2003

Monitoring the ubiquitin/proteasome system in conformational diseases.

Controlled proteolysis of regulatory or aberrant proteins by the ubiquitin/proteasome system is indispensable for cell viability. Conformational diseases such as Alzheimer's, Parkinson's and Huntington's disease are characterised by the accumulation of misfolded or aggregation-prone proteins. Since these proteins are typical substrates of the ubiquitin/proteasome system, it is not surprising that various models propose impairment of this system as a contributing factor to the pathology of conformational disorders. The complex nature of the ubiquitin/proteasome system and its universal role in cell physiology however turns evaluation of these attractive hypotheses into a major challenge. Several reporter substrates for the ubiquitin/proteasome system have recently been developed to facilitate functional studies of the system in living cells. In this review, we will discuss these new tools as well as the proteins associated with conformational disease that have been studied with these reporters.

Animals↗

PubMed2005

Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: implications for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive amnestic disorder typified by the pathological misfolding and deposition of the microtubule-associated tau protein into neurofibrillary tangles (NFTs). While numerous post-translational modifications influence NFT formation, the molecular mechanisms responsible for tau aggregation remain enigmatic. Since nitrative and oxidative injury have previously been shown to play a mechanistic role in neurodegeneration, we examined whether these events influence tau aggregation. In this report, we characterize the effects of peroxynitrite (ONOO-)-mediated nitration and oxidation on tau polymerization in vitro. Treatment of tau with ONOO- results in 3-nitrotyrosine (3-NT) immunoreactivity and the formation of heat-stable, SDS-insoluble oligomers. Using ESI-MS and HPLC with fluorescent detection, we show that these higher-order aggregates contain 3,3'-dityrosine (3,3'-DT). Tyrosine (Tyr) residues are critical for ONOO(-)-mediated oligomerization, as tau proteins lacking all Tyr residues fail to generate oligomers upon ONOO- treatment. Further, tau nitration targets residues Y18, Y29, and to a lesser degree Y197 and Y394, and nitration at these sites inhibits in vitro polymerization. The inhibitory effect of nitration on tau polymerization is specific for the 3-NT modification, as pseudophosphorylation at these same Tyr residues does not inhibit tau assembly. Our results suggest that the nitrative and oxidative roles of ONOO- differentially affect tau polymerization and that ONOO(-)-mediated cross-linking could facilitate tau aggregation in AD.

Alzheimer Disease↗

PubMed1976

The significance of plasma lipoproteins on erythrocyte aggregation and sedimentation.

Increased erythrocyte aggregation can be induced by high concentrations of human lipoproteins. The dependence of aggregate formation on lipoprotein concentration was recorded by determination of erythrocyte sedimentation rate (ESR), by electrical measurement of the erythrocyte aggregation index (EAI) and by scanning electron microscopy. The lipoprotein concentrations necessary to induce a significantly increased ESR in an otherwise normal human plasma are much too high to be encountered in physiologic or even severe pathologic states. Therefore hyperlipoproteinaemia by itself cannot explain a raised ESR. In cases where the ESR is raised due to the presence of increased amounts of other erythrocyte aggregating plasma proteins (agglomerins), hyperlipoproteinaemia can contribute to a limited extent to the increase in ESR. The possible pathophysiological significance of the demonstrated erythrocyte aggregating capacity of human lipoproteins in a microvascular environment is noted.

Blood Sedimentation↗

PubMed2003

Platelets and anti-platelet therapy.

Platelets play a central role in the hemostatic process and consequently are similarly involved in the pathological counterpart, thrombosis. They adhere to various subendothelial proteins, exposed either by injury or disease, and subsequently become activated by the thrombogenic surface or locally produced agonists. These activated platelets aggregate to form a platelet plug, release agonists which recruit more platelets to the growing thrombus, and provide a catalytic surface for thrombin generation and fibrin formation. These platelet-rich thrombi are responsible for the acute occlusion of stenotic vessels and ischemic injury to heart and brain. A range of anti-platelet drugs are currently used, both prophylactically and therapeutically, in regimens to manage thrombo-embolic disorders. These include inhibitors of the generation, or effects, of locally produced agonists; several large clinical trials have supported roles for cyclooxygenase inhibitors, which prevent thromboxane generation, and thienopyridine derivatives, which antagonize ADP receptors. Similarly intravenous alpha IIb beta 3 antagonists have been shown to be effective anti-thrombotics, albeit in highly selective situations; in contrast, to date studies with their oral counterparts have been disappointing. Recent advances in understanding of platelet physiology have suggested several novel, if yet untested, targets for anti-platelet therapy. These include the thrombin receptor, the serotonin handling system, and the leptin receptor.

Animals↗

PubMed2006

Potential compensatory responses through autophagic/lysosomal pathways in neurodegenerative diseases.

Intracellular protein degradation decreases with age, altering the important balance between protein synthesis and breakdown. Slowly, protein accumulation events increase causing axonopathy, synaptic deterioration, and subsequent cell death. As toxic species accumulate, autophagy-lysosomal protein degradation pathways are activated. Responses include autophagic vacuoles that degrade damaged cellular components and long-lived proteins, as well as enhanced levels of lysosomal hydrolases. Although such changes correlate with neuronal atrophy in age-related neurodegenerative disorders and in related models of protein accumulation, the autophagic/lysosomal responses appear to be compensatory reactions. Recent studies indicate that protein oligomerization/ aggregation induces autophagy and activates lysosomal protein degradation in an attempt to clear toxic accumulations. Such compensatory responses may delay cell death and account for the gradual nature of protein deposition pathology that can extend over months/years in model systems and years/decades in the human diseases. Correspondingly, enhancement of compensatory pathways shifts the balance from pathogenesis to protection. Positive modulation of protein degradation processes represents a strategy to promote clearance of toxic accumulations and to slow the synaptopathogenesis and associated cognitive decline in aging-related dementias.

Aging↗

PubMed2007

The role of tau phosphorylation and cleavage in neuronal cell death.

The microtubule-associated protein tau is the primary component of the intracellular filamentous deposits found in Alzheimer's disease (AD) brain and also in a family of neurodegenerative diseases called 'tauopathies', where tau pathology is the primary, defining characteristic with little or no amyloid-beta (Abeta) pathology. It has been demonstrated that tau modifications such as hyperphosphorylation and truncation might be important events in the process leading to tau intracellular aggregation and neuronal cell death. The discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders. This review highlights recent findings concerning the normal metabolism and function of tau, as well as the abnormal processing and function of tau in AD and in the tauopathies.

Alternative Splicing↗

PubMed2005

Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein.

Mice overexpressing mutant alpha-synuclein develop a progressive loss of motor function associated with the accumulation of aggregated alpha-synuclein in neurons of the brainstem. Recent reports suggest that tau pathology might also be associated with Parkinson disease (PD) and aggregation of alpha-synuclein. We now report that mice overexpressing A30P alpha-synuclein develop abnormally phosphorylated tau in parallel with the accumulation of aggregated alpha-synuclein. Enhanced phosphorylation of tau occurs only in symptomatic mice that also harbor abundant aggregated alpha-synuclein. The increased phosphorylation of tau occurs at S396/404 and S202 as shown by immunoblotting and immunocytochemical studies with the antibodies PHF-1 and AT8. Neurons that accumulated alpha-synuclein occurred in the dorsal brainstem and did not show strong colocalization with neurons that showed abnormal tau phosphorylation, which largely occurred in the ventral brainstem. Aggregation of alpha-synuclein and phosphorylation of tau are associated with increased levels of phosphorylated c-jun kinase (JNK), which is a stress kinase known to phosphorylate tau protein. These results suggest that alpha-synuclein pathology can stimulate early pathological changes in tau.

Age Factors↗

PubMed1999

In vitro evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease.

A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in affected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from in vivo and in vitro studies of mutant huntingtin have lead to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington's disease (HD). We tested this hypothesis using a 293T cell culture model system that compared the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. We first assessed the mode of nuclear transport of N-terminal fragments of huntingtin, and show that the predicted endogenous NLS is not functional, providing data in support of passive nuclear transport. This result suggests that proteolysis is a necessary step for nuclear entry of huntingtin. Additionally, insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not influence their total aggregate frequency. There were also no significant differences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. The findings of nuclear and cytoplasmic aggregates in affected brains, together with these in vitro data, support the nucleus and cytosol as subcellular sites for pathogenesis in HD.

Amino Acid Sequence↗

PubMed1996

The molecular pathology of hereditary cystatin C amyloid angiopathy causing brain hemorrhage.

Knowledge about molecular pathology of hereditary cystatin C amyloid angiopathy (HCCAA), also called hereditary cerebral hemorrhage with amyloidosis, Icelandic type, has increased greatly in the last decade. The disorder has an autosomal dominant mode of inheritance and causes fatal brain hemorrhage in normotensive young adults. It is due to a mutation in the gene encoding the cysteine proteinase inhibitor, cystatin C.A single nucleotide is substituted, A for T, in the codon 68, resulting in glutamine replacing leucine in the protein sequence. This variant protein has an increased tendency to aggregate and forms heavy depositions of amyloid in the walls of the small arteries and arterioles of the brain. The amyloid deposition leads to arterial damage with single or multiple strokes. In the following review the clinical features, family studies, pathology, biochemistry and molecular genetics of HCCAA are addressed.

Adolescent↗

PubMed2005

Forcing nonamyloidogenic beta-synuclein to fibrillate.

The fibrillation and aggregation of alpha-synuclein is a key process in the formation of intracellular inclusions, Lewy bodies, in substantia nigral neurons and, potentially, in the pathology of Parkinson's disease and several other neurodegenerative disorders. Alpha-synuclein and its homologue beta-synuclein are both natively unfolded proteins that colocalize in presynaptic terminals of neurons in many regions of the brain, including those of dopamine-producing cells of the substantia nigra. Unlike its homologue, beta-synuclein does not form fibrils and has been shown to inhibit the fibrillation of alpha-synuclein. In this study, we demonstrate that fast and efficient aggregation and fibrillation of beta-synuclein can be induced in the presence of a variety of factors. Certain metals (Zn(2+), Pb(2+), and Cu(2+)) induce a partially folded conformation of beta-synuclein that triggers rapid fibrillation. In the presence of these metals, mixtures of alpha- and beta-synucleins exhibited rapid fibrillation. The metal-induced fibrillation of beta-synuclein was further accelerated by the addition of glycosaminoglycans or high concentrations of macromolecular crowding agents. Beta-synuclein also rapidly formed soluble oligomers and fibrils in the presence of pesticides, whereas the addition of low concentrations of organic solvents induced formation of amorphous aggregates. These new findings demonstrate the potential effect of environmental pollutants in generating an amyloidogenic, and potentially neurotoxic, conformation, in an otherwise benign protein.

Amyloid↗

PubMed1993

Purification and characterization of hyaluronan from synovial fluid.

An easy and rapid method for the purification and characterization of hyaluronan from synovial fluid has been developed. Lipids were removed by filtration through a hydrophobic filter prior to the removal of proteins by phenol-chloroform extraction. The hyaluronan recovery was 95%, as measured by three different methods. The average molecular weight of hyaluronan did not change during the purification. Furthermore, it was found that an optimized enzymatic protein digestion of pathological human synovial fluid prior to filtration yielded up to five times more hyaluronan recovered. In addition, the molecular weight of hyaluronan from synovial fluid not digested with pronase E was apparently higher because of the presence of aggregates. After the purification of hyaluronan (ca. 15 min), a single size-exclusion chromatography step allowed the simultaneous determination of its concentration and the reasonable estimate of its average molecular weight and molecular weight distribution curve. The logarithm of the molecular weight showed a linear dependence on the size-exclusion chromatography elution volume for hyaluronan in the molecular weight range 2.0 x 10(6)-1.0 x 10(4). The removal of proteins allowed the determination of fairly low-molecular-weight fractions of hyaluronan, compared to untreated samples for which hyaluronan and protein peaks partially overlap.

Chromatography, Gel↗