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PubMedDate not supplied

Role of oxidative damage in protein aggregation associated with Parkinson's disease and related disorders.

Parkinson's disease, the most common movement disorder, is characterized by the loss of brainstem neurons, specifically dopaminergic neurons in the substantia nigra, as well as the accumulation of neuronal cytoplasmic filamentous proteinaceous inclusions comprised of polymerized alpha-synuclein. It was reported recently that alpha-synuclein can induce the formation of filamentous tau inclusions, which are characteristic of disorders like Alzheimer's disease and Lewy body variant of Alzheimer's disease, suggesting that a similar mechanism may exist between alpha-synuclein fibrillogenesis and tau polymerization. Pathological brain inclusions comprised of alpha-synuclein or tau proteins are associated with a spectrum of neurodegenerative disorders, and oxidative and nitrative injury has been implicated in all of these diseases. However, the role of oxidative damage in alpha-synuclein and tau polymerization and pathological inclusion formation is complex. Differences in the level, type, and temporal sequence of the oxidative alterations appear to result in both inhibitory and stimulatory effects on the fibrillogenesis of these proteins.

Animals↗
PubMed2005

Oxidative metabolites accelerate Alzheimer's amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation.

The process of amyloid formation by the amyloid beta peptide (Abeta), i.e., the misassembly of Abetapeptides into soluble quaternary structures and, ultimately, amyloid fibrils, appears to be at the center of Alzheimer's disease (AD) pathology. We have shown that abnormal oxidative metabolites, including cholesterol-derived aldehydes, modify Abeta and accelerate the early stages of amyloidogenesis (the formation of spherical aggregates). This process, which we have termed metabolite-initiated protein misfolding, could explain why hypercholesterolemia and inflammation are risk factors for sporadic AD. Herein, the mechanism by which cholesterol metabolites hasten Abeta 1-40 amyloidogenesis is explored, revealing a process that has at least two steps. In the first step, metabolites modify Abeta peptides by Schiff base formation. The Abeta-metabolite adducts form spherical aggregates by a downhill polymerization that does not require a nucleation step, dramatically accelerating Abeta aggregation. In agitated samples, a second step occurs in which fibrillar aggregates form, a step also accelerated by cholesterol metabolites. However, the metabolites do not affect the rate of fibril growth in seeded aggregation assays; their role appears to be in initiating amyloidogenesis by lowering the critical concentration for aggregation into the nanomolar range. Small molecules that block Schiff base formation inhibit the metabolite effect, demonstrating the importance of the covalent adduct. Metabolite-initiated amyloidogenesis offers an explanation for how Abeta aggregation could occur at physiological nanomolar concentrations.

Alzheimer Disease↗
PubMed1998

Detection of single amyloid beta-protein aggregates in the cerebrospinal fluid of Alzheimer's patients by fluorescence correlation spectroscopy.

Alzheimer's disease is associated with the intraparenchymal growth of plaque-like amyloid deposits. Amyloid plaques are formed by the progressive deposition and transformation of soluble amyloid beta-protein monomers into insoluble and fibrillar aggregates that contain amyloid beta-protein in a beta-pleated sheet conformation. This process is described as 'seeded polymerization' of the monomers with slow-nucleation and fast-growth kinetics. Soluble amyloid beta-protein monomers are present in the cortical extracellular space and in the cerebrospinal fluid, whereas insoluble aggregates so far can be found only by the examination of brain tissue by biopsy or autopsy. Here we present a biophysical method that uses the principle of seeded polymerization in combination with fluorescence correlation spectroscopy, which allowed us to detect single amyloid beta-peptide aggregates in the cerebrospinal fluid samples from Alzheimer's patients. All of 15 Alzheimer's samples but none of the 19 age-matched control samples produced large peaks with fluorescence correlation spectroscopy indicating the rapid aggregation of the fluorescent labelled synthetic amyloid beta-protein probe onto the amyloid beta-protein 'seeds' present in the cerebrospinal fluid. Our method could enable easy in vivo detection of the cerebral amyloid beta-protein pathology of Alzheimer's disease and might be of potential value to facilitate its routine diagnosis.

Aged↗
PubMed2002

Hyaluronate degradation as an alternative mechanism for proteoglycan release from cartilage during interleukin-1beta-stimulated catabolism.

Data presented previously suggest that release of components of the cartilage matrix, in response to catabolic agents, cannot be accounted for by proteolytic mechanisms alone. In the present study, the release of glycosaminoglycan-containing components from bovine nasal cartilage cultured in the presence of interleukin-1beta, and from bovine nasal, fetal bovine epiphyseal and adult human articular cartilage cultured in the presence of retinoic acid, was accompanied by the loss of link protein and hyaluronate into the culture medium. Chromatographic analysis of the released hyaluronate showed it to be markedly reduced in size relative to that extracted from the corresponding tissue. It is proposed that, under stimulation by catabolic agents, two independent, but concurrent, mechanisms act to promote the release of aggrecan from the cartilage matrix. First, proteolytic cleavage of the aggrecan core protein results in the production of glycosaminoglycan-containing fragments that are free to diffuse from the tissue. Secondly, cleavage of hyaluronate renders portions of the proteoglycan aggregate small enough so that complexes of aggrecan (or fragments containing its G1 domain) and link protein are released from the tissue. It is likely that both mechanisms contribute to cartilage metabolism in normal physiology and pathology.

Animals↗
PubMed2001

Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors.

Mitochondrial dysfunction has been associated with Parkinson's disease. However, the role of mitochondrial defects in the formation of Lewy bodies, a pathological hallmark of Parkinson's disease has not been addressed directly. In this report, we investigated the effects of inhibitors of the mitochondrial electron-transport chain on the aggregation of alpha-synuclein, a major protein component of Lewy bodies. Treatment with rotenone, an inhibitor of complex I, resulted in an increase of detergent-resistant alpha-synuclein aggregates and a reduction in ATP level. Another inhibitor of the electron-transport chain, oligomycin, also showed temporal correlation between the formation of aggregates and ATP reduction. Microscopic analyses showed a progressive evolution of small aggregates of alpha-synuclein to a large perinuclear inclusion body. The inclusions were co-stained with ubiquitin, 20 S proteasome, gamma-tubulin, and vimentin. The perinuclear inclusion bodies, but not the small cytoplasmic aggregates, were thioflavin S-positive, suggesting the amyloid-like conformation. Interestingly, the aggregates disappeared when the cells were replenished with inhibitor-free medium. Disappearance of aggregates coincided with the recovery of mitochondrial metabolism and was partially inhibited by proteasome inhibitors. These results suggest that the formation of alpha-synuclein inclusions could be initiated by an impaired mitochondrial function and be reversed by restoring normal mitochondrial metabolism.

Adenosine Triphosphate↗
PubMed2004

Natural antioxidants and neurodegenerative diseases.

Neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD) diseases are defined by a progressive neuronal dysfunction and an ensuing behavioral dysfunction. Although protein aggregation (i.e beta-amyloid and alpha-synuclein) plays a pivotal role in both AD and PD, there is increasing evidence that excessive accumulation of reactive oxygen species (ROS) that occurs during normal and pathological brain aging contributes to neuronal losses and dysfunction. Based on these observations, it has been hypothesized that natural antioxidants derived from food, beverages and natural extracts may be beneficial to prevent or delay the occurrence of age-related cognitive deficits and neurodegenerative diseases. We will summarize in this review the role of oxidative stress in pathological brain aging, and provide evidence for a role for antioxidant molecules as therapeutic agents. We will also focus on the various mechanisms underlying their neuroprotective effects in in vivo and in vitro models of neurotoxicity.

Acetylcarnitine↗
PubMed2000

Detection of red cell aggregation by low shear rate viscometry in whole blood with elevated plasma viscosity.

The viscosity of whole blood measured at low shear rates is determined partly by shear resistance of the red cell aggregates present, stronger aggregation increasing the viscosity in the absence of other changes. Effects of cell deformability can confound interpretation and comparison in terms of aggregation, however, particularly when the plasma viscosity is high. We illustrate the problem with a comparison of hematocrit-adjusted blood from type 1 diabetes patients and controls in which it is found the apparent and relative viscosities at a true shear rate of 0.20 s-1 are lower in the patient samples than age matched controls, in spite of reports that aggregation is increased in such populations. Because the plasma viscosities of the patients were higher on average than controls, we performed a series of experiments to examine the effect of plasma protein concentration and viscosity on normal blood viscosity. Dilution or concentration by ultrafiltration of autologous plasma and viscosity measurements at low shear on constant hematocrit red cell suspensions showed (a) suspension viscosity at 0.25 and 3 s-1 increased monotonically with plasma protein concentration and viscosity but (b) the relative viscosity increased, in concert with the microscopic aggregation grade, up to a viscosity of approximately 1.25 mPa-s but above this the value the relative viscosity no longer increased as the degree of aggregation increased in concentrated plasmas. It is suggested that in order to reduce cell deformation effects in hyperviscous pathological plasmas, patient and control plasmas should be systematically diluted before hematocrit is adjusted and rheological measurements are made. True shear rates should be calculated. Comparison of relative viscosities at low true shear rates appears to allow the effects of red cell aggregation to be distinguished by variable shear rate viscometry in clinical blood samples.

Adult↗
PubMed2006

Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways.

Diversity and intensity of intellectual and physical activities seem to have an inverse relationship with the extent of cognitive decline in Alzheimer's disease (AD). To study the interaction between an active lifestyle and AD pathology, female TgCRND8 mice carrying human APPswe+ind were transferred into enriched housing. Four months of continuous and diversified environmental stimulation resulted in a significant reduction of beta-amyloid (Abeta) plaques and in a lower extent of amyloid angiopathy. Neither human amyloid precursor protein (APP) mRNA/protein levels nor the level of carboxy-terminal fragments of APP nor soluble Abeta content differed between both groups, making alterations in APP expression or processing unlikely as a cause of reduced Abeta deposition. Moreover, DNA microarray analysis revealed simultaneous down-regulation of proinflammatory genes as well as up-regulation of molecules involved in anti-inflammatory processes, proteasomal degradation, and cholesterol binding, possibly explaining reduced Abeta burden by lower aggregation and enhanced clearance of Abeta. Additionally, immunoblotting against F4/80 antigen and morphometric analysis of microglia (Mac-3) revealed significantly elevated microgliosis in the enriched brains, which suggests increased amyloid phagocytosis. In summary, this study demonstrates that the environment interacts with AD pathology at dif-ferent levels.

Amyloid beta-Protein Precursor↗
PubMed2002

Formation of Hirano bodies in Dictyostelium and mammalian cells induced by expression of a modified form of an actin-crosslinking protein.

We report the serendipitous development of the first cultured cell models of Hirano bodies. Myc-epitope-tagged forms of the 34 kDa actin bundling protein (amino acids 1-295) and the CT fragment (amino acids 124-295) of the 34 kDa protein that exhibits activated actin binding and calcium-insensitive actin filament crosslinking activity were expressed in Dictyostelium and mammalian cells to assess the behavior of these modified forms in vivo. Dictyostelium cells expressing the CT-myc fragment: (1) form ellipsoidal regions that contain ordered assemblies of F-actin, CT-myc, myosin II, cofilin and alpha-actinin; (2) grow and develop more slowly than wildtype, but produce normal morphogenetic structures; (3) perform pinocytosis and phagocytosis normally; and (4) produce a level of total actin equivalent to wildtype, but a higher level of F-actin. The paracrystalline inclusions bear a striking resemblance to Hirano bodies, which are associated with a number of pathological conditions. Furthermore, expression of the CT fragment in murine L cells results in F-actin rearrangements characterized by loss of stress fibers, accumulation of numerous punctate foci, and large perinuclear aggregates, the Hirano bodies. Thus, failure to regulate the activity and/or affinity of an actin crosslinking protein can provide a signal for formation of Hirano bodies. More generally, formation of Hirano bodies is a cellular response to or a consequence of aberrant function of the actin cytoskeleton. The results reveal that formation of Hirano bodies is not necessarily related to cell death. These cultured cell models should facilitate studies of the biochemistry, genetics and physiological effects of Hirano bodies.

Actins↗
PubMed2002

Cerebellar cortical tau pathology in progressive supranuclear palsy and corticobasal degeneration.

Immunohistochemical localization of tau in the cerebellar cortex was carried out using a mouse monoclonal antibody against phosphorylation-dependent tau (AT8) in brain tissue (cerebellum) from 13 patients with progressive supranuclear palsy (PSP), 7 patients with corticobasal degeneration (CBD) and 5 age-matched control subjects. Purkinje cell somata that showed diffuse granular accumulation of cytoplasmic tau were found occasionally in 9 of the 13 patients with PSP (69%) and in 4 of the 7 patients with CBD (57%). Tau-positive doughnut-shaped structures were also found occasionally in the cerebellar molecular layer in 6 of the 13 patients with PSP (46%) and 2 of the 7 patients with CBD (29%). No tau immunoreactivity was detected in the cerebellar cortex in the control tissue. In the tissue from one patient with PSP, we also performed a double-labeling immunofluorescence study with anti-glial fibrillary acidic protein (GFAP) antibody and AT8, as well as an immuno-electron microscopic study with AT8. In tau-positive Purkinje cell somata and dendrites, the reaction product was localized mainly within the rough endoplasmic reticulum and free ribosomes. Tau-positive doughnut-shaped structures were located in the GFAP-positive radial processes of Bergmann's glia and were present in the outer areas of inclusions reminiscent of Lewy bodies, which consist of aggregated pathological tau filaments. In conclusion, we have demonstrated a novel tau pathology that affects Purkinje cells and Bergmann's glia in patients with PSP and CBD, indicating that the cerebellar cortex can be involved in the disease processes in PSP and CBD.

Aged↗
PubMed2004

The role of pre-existing aggregates in Hsp104-dependent polyglutamine aggregate formation and epigenetic change of yeast prions.

Amyloid-like protein aggregates have been implicated in various diseases and in the protein-based inheritance of yeast prions. The molecular chaperone Hsp104 has been shown to be necessary for the aggregate formation of polyglutamine in yeast, and for the maintenance of several yeast prion phenotypes through the formation of self-propagating aggregates. In this paper, we show that the polyglutamine aggregates that are formed independently of Hsp104, are required for Hsp104 to efficiently produce more aggregates. Similarly, in the yeast prion [PSI+] system, Hsp104-dependent epigenetic changes to the [PSI+] prion phenotype require the presence of prion aggregates in the normal [psi-] state. We also show that the co-localization of different prion aggregates suggests that cross-seeding by different yeast prions increases the probability of Hsp104-dependent epigenetic change. These findings highlight the role of pre-existing aggregates in chaperone-dependent establishment of the epigenetic trait in yeast prions, and possibly in the pathology of several neurodegenerative diseases.

Epigenesis, Genetic↗
PubMed1997

A possible dual physiological role of extracellular ATP in the modulation of platelet aggregation.

ATP and ADP are simultaneously released from activated platelets in equimolar concentrations. Micromolar concentrations of ATP inhibit platelet aggregation by both competitive and non-competitive mechanisms. The current studies addressed the question of how platelets respond to agonists in the presence of nanomolar and micromolar concentrations of ATP and ADP alone or in combination. This is a significant issue since the concentration of ATP +/- ADP may vary widely within a microenvironment depending upon the source and cause for the release of the nucleotides. ATP (1-10 nM) was found to significantly enhance the thromboxane A2 analog, U44619-, collagen- and thrombin-induced platelet aggregations. Conversely, ATP at 1-100 microM inhibited these same reactions. ADP, in general, behaved exactly opposite to ATP. When equal amounts of ATP and ADP were added together the ADP response appeared to predominate. The observed ATP-induced response was not due to a hydrolytic product as evidenced by an unaltered response to ATP in the presence of adenosine deaminase or the ATP generating system, creatine phosphate plus creatine phosphokinase. Adenosine (1-10 nM), like ADP, inhibited agonist-induced platelet aggregation. The stimulation of agonist-induced platelet aggregation by 1-10 nM extracellular ATP appears to depend upon the phosphorylation of platelet membrane ecto proteins. The ATP analog, beta gamma-methylene ATP, that is incapable of serving as a phosphate donor for protein kinases, inhibited rather than stimulated agonist-induced platelet aggregation. The dual response of platelets to low and high concentrations of extracellular ATP +/- ADP may play a physiological role in hemostasis and thrombosis under normal and pathological conditions.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2003

The hydrophobic internal region of bovine prion protein shares structural and functional properties with HIV type 1 fusion peptide.

The conserved fusion peptide at the N-terminus of HIV-1 envelope glycoprotein gp41 is involved in the virus-cell fusion reaction and in the cytopathic effects promoted by expression in single cells. The conserved bovine prion protein 121KHVAGAAAAGAVVGGLGGYMLGSAMSR147 transmembrane region (BPrP(tm)) contains a sequence rich in Gly residues [i.e., 130GAVVGGLGGYMLGSAMSR147 (BPrP(mi))] that shows homology with HIV-1 fusion peptide. As in the case of the latter peptide, analysis of the BPrP(mi) interfacial hydrophobicity confirms that this stretch bears an intrinsic tendency to partitioning from the aqueous phase into membranes. Experimental analyses of BPrP(mi)-lipid interactions suggest several similarities between this sequence and HIV-1 fusion peptide. Infrared spectroscopy reveals a conformational plasticity of the membrane-associated prion sequence comparable to that displayed by the viral sequence. The adoption of a mainly alpha-helical structure correlates with the formation of lytic pores. This helical structure can be converted into a beta-sheet conformation by addition of calcium, a process that is accompanied by vesicle membrane fusion. In contrast, transmembrane BPrP(tm) associates with membranes in a nonlytic, mainly helical structure but also containing some random coil. Upon addition of calcium, the random coils disappear while the helical conformation remains. In the absence of membranes both prion and HIV-1 sequences form amyloid-type fibers. It is proposed that during the pathological processes induced by secreted PrPSc and its proteolytic fragments, conformational polymorphism displayed by membrane-inserted BPrP(mi) may play a role at perturbing the general architecture of the membrane lipid bilayer and inducing protein-protein aggregation at membrane surfaces. These findings suggest the existence of common mechanisms underlying cytotoxicity by PrP and HIV-1 gp41.

Amino Acid Sequence↗
PubMed2005

Molecular pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the population over the age of 65. Despite a well-described clinical and pathological phenotype, the molecular mechanisms which lead to neurodegeneration remain elusive. However, there is a wealth of evidence from both toxin based models and genetic based models, which suggest a major etiologic role for mitochondrial dysfunction, protein aggregation, the ubiquitin-proteasome system and kinase signalling pathways in the pathogenesis of PD. Ultimately, an understanding of the molecular events which precipitate neurodegeneration in idiopathic PD will enable the development of targeted and effective therapeutic strategies. We review the latest evidence for the proposed molecular processes and discuss their relevance to the pathogenesis of sporadic PD.

Humans↗
PubMed2006

Heart failure and protein quality control.

The heart is constantly under mechanical, metabolic, and thermal stress, even at baseline physiological conditions, and cardiac stress may increase as a result of environmental or intrinsic pathological insults. Cardiomyocytes are continuously challenged to efficiently and properly fold nascent polypeptides, traffic them to their appropriate cellular locations, and keep them from denaturing in the face of normal and pathological stimuli. Because deployment of misfolded or unfolded proteins can be disastrous, cells, in general, and cardiomyocytes, in particular, have developed a multilayered protein quality control system for maintaining proper protein conformation and for reorganizing and removing misfolded or aggregated polypeptides. Here, we examine recent data pointing to the importance of protein quality control in cardiac homeostasis and disease.

Animals↗
PubMed2005

Molecular pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the population over the age of 65. Despite a well-described clinical and pathological phenotype, the molecular mechanisms which lead to neurodegeneration remain elusive. However, there is a wealth of evidence from both toxin based models and genetic based models, which suggest a major etiologic role for mitochondrial dysfunction, protein aggregation, the ubiquitin-proteasome system and kinase signalling pathways in the pathogenesis of PD. Ultimately, an understanding of the molecular events which precipitate neurodegeneration in idiopathic PD will enable the development of targeted and effective therapeutic strategies. We review the latest evidence for the proposed molecular processes and discuss their relevance to the pathogenesis of sporadic PD.

Animals↗
PubMed1989

[Rheologic findings in patients with Eales disease].

In a retrospective analysis of findings in 12 patients with Eales' disease significant changes in blood fluidity were established. The six female and six male patients, aged between 15 and 59, were examined in the acute and subclinical stages and when a recurrence occurred. The rheologic parameters plasma viscosity, erythrocyte rigidity, and erythrocyte aggregation were significantly increased in the acute stage and when there was a recurrence, while in the subclinical stage the rheologic values improved to normal. No correlation could be found between the severity of the clinical picture in the various phases and the rheologic values. None of the other biochemical, microbiologic, and immunologic parameters were pathologic in any stage of the disease. In particular, virus serology, protein, immune, and hemoglobin electrophoresis were normal in all patients. While the etiology of Eales' disease remains unknown, deteroration in erythrocyte rigidity appears to play a part in the pathophysiology of the disease.

Adolescent↗