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Results for “Protein Aggregation, Pathological”

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PubMed2004

More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases.

Intracytoplasmic filamentous aggregates, such as neurofibrillary tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease, are composed of the proteins tau and alpha-synuclein, respectively. These pathological inclusions are linked directly to the etiology and mechanisms of disease in a wide spectrum of neurodegenerative disorders, termed 'tauopathies' and 'synucleinopathies'. Emerging evidence indicates that there is frequent overlap of the pathological and clinical features of patients with tauopathies and synucleinopathies, thereby re-enforcing the notion that these disorders might be linked mechanistically. Indeed, several lines of investigation suggest that tau and alpha-synuclein might constitute a unique class of unstructured proteins that assemble predominantly into homopolymeric (rather than heteropolymeric) fibrils, which deposit mainly in separate amyloid inclusions, but occasionally deposit together. Thus, the ability of tau and alpha-synuclein to affect each other directly or indirectly might contribute to the overlap in the clinical and pathological features of tauopathies and synucleinopathies.

Amyloid↗

PubMed2001

[Alzheimer's disease in the year 2000].

This document summarizes a report on the current state of knowledge of the etiology, diagnosis, and treatment of Alzheimer's disease and on the primary research activities carried out in these areas during the year 2000 under the auspices of the National Institute of Aging and other units of the National Institutes of Health (NIH) of the United States of America. In research on the etiology of the disease, key areas of attention have included amyloid, presenilins, apolipoprotein E, and other genetic ties; apoptosis; and protein aggregation in other neurodegenerative disease. With respect to diagnosis, the progress that has been made is analyzed in the areas of neuroimaging and neuropsychological tests, clinical-pathological correlations, and the identification of biological disease markers, with the goal of being able to diagnose the disease before irreversible cognitive and functional deterioration takes place. Research on pharmacological treatment has been centered on three primary concerns: short-term maintenance of cognitive function, disease prevention, and treatment of behavioral symptoms. Another subject of great importance is support for those who provide care for patients. The report also deals with several areas related to research infrastructure and the contributions of other units of the NIH.

Aged↗

PubMed1999

From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is an inherited progressive neurodegenerative disease caused by the expansion of a polyglutamine repeat sequence within a novel protein. Recent work has shown that abnormal intranuclear inclusions of aggregated mutant protein within neurons is a characteristic feature shared by HD and several other diseases involving glutamine repeat expansion. This suggests that in each of the these disorders the affected nerve cells degenerate as a result of these abnormal inclusions. A transgenic mouse model of HD has been generated by introducing exon 1 of the HD gene containing a highly expanded CAG sequence into the mouse germline. These mice develop widespread neuronal intranuclear inclusions and neurodegeneration specifically within those areas of the brain known to degenerate in HD. We have investigated the sequence of pathological changes that occur after the formation of nuclear inclusions and that precede neuronal cell death in these cells. Although the relation between inclusion formation and neurodegeneration has recently been questioned, a full characterization of the pathways linking protein aggregation and cell death will resolve some of these controversies and will additionally provide new targets for potential therapies.

Animals↗

PubMedDate not supplied

[Phosphorylation of tau and Alzheimer's disease].

Tau is an important component of neuronal cytosqueleton; the protein stabilizas microtubules, maintains cell shape and axonal transport mechanisms. However, for unknown reasons tau experiments important postranslation modifications including enhanced phosphorilation due to unbalanced activity between kinases and phosphatases, affecting its normal biological function. Under these circumstances tau begins to aggregate into neurofibrillary tangles (NFTS) complexes which are pathological hallmarks of Alzheimer's disease together with senile plaques. This review is mainly concerned with the role that different kinase play into the regulation of tau structure and function.

Alzheimer Disease↗

PubMed2005

Protein amyloidose misfolding: mechanisms, detection, and pathological implications.

A variety of diseases result because of misfolded protein that deposits in extracellular space in the body. These deposits can be amorphous (disordered) or fibrillar (ordered). Inclusion bodies are an example of amorphous aggregates, and amyloid fibril is an example of fibrillar or ordered aggregates. In this chapter, we discuss a class of diseases caused by fibrillar aggregate deposits or amyloid fibrils called amyloidosis. We also review mechanisms by which different proteins misfold to form amyloid fibrils. Each amyloid fibril formed from a different protein causes a different disease by affecting a different organ in the body. However, the characteristics of different amyloid fibrils, namely structure and morphology, observed by electron microscopy and X-ray fiber diffraction appear to be quite similar in nature. We present therapeutic strategies developed to eliminate amyloid fibril formation. These strategies could possibly avert a whole class of fatal diseases caused by amyloid fibril deposition owing to similar characteristics of the amyloid fibrils.

Alzheimer Disease↗

PubMed2005

Coincident thresholds of mutant protein for paralytic disease and protein aggregation caused by restrictively expressed superoxide dismutase cDNA.

Familial amyotrophic lateral sclerosis (FALS) has been modeled in transgenic mice by introducing mutated versions of human genomic DNA encompassing the entire gene for Cu,Zn superoxide dismutase (SOD1). In this setting, the transgene is expressed throughout the body and results in mice that faithfully recapitulate many pathological and behavioral aspects of FALS. By contrast, transgenic mice made by introducing recombinant vectors, encoding cDNA genes, that target mutant SOD1 expression to motor neurons, only, or astrocytes, only, do not develop disease. Here, we report that mice transgenic for human SOD1 cDNA with the G37R mutation, driven by the mouse prion promoter, develop motor neuron disease. In this model, expression of the transgene is highest in CNS (both neurons and astrocytes) and muscle. The gene was not expressed in cells of the macrophage lineage. Although the highest expressing hemizygous transgenic mice fail to develop disease by 20 months of age, mice homozygous for the transgene show typical ALS-like phenotypes as early as 7 months of age. Spinal cords and brain stems from homozygous animals with motor neuron disease were found to contain aggregated species of mutant SOD1. The establishment of this SOD1-G37R cDNA transgenic model indicates that expression of mutant SOD1 proteins in the neuromuscular unit is sufficient to cause motor neuron disease. The expression levels required to induce disease coincide with the levels required to induce the formation of SOD1 aggregates.

Amyotrophic Lateral Sclerosis↗

PubMed1987

Signal transduction in normal and pathological thrombin-stimulated human platelets.

Human blood platelets stimulated by thrombin undergo very rapid morphological changes, the most characteristic of which are pseudopod formation and granule centralization. These early changes in shape are accompanied by a transient decrease (30%) in phosphatidyl inositol 4,5-bisphosphate (PIP2) which occurs in the first 10 s after thrombin addition. Transient decreases in phosphatidyl inositol 4-phosphate (PIP) and phosphatidyl inositol (PI) occur later (20-30 s). These events lead to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DG) and hence phosphatidate (PA). Two polypeptides are phosphorylated during the same time span: the myosin light chain (P20) and a 43 kDa protein (P43). Concomitant with these molecular changes, platelet 'release reaction' occurs, i.e., liberation of the different granule constituents into the external medium: the earliest concerns dense bodies which liberate adenine nucleotides, calcium and serotonin; alpha-granules then liberate adhesive and specific proteins and are followed by lysosomes which liberate hydrolases. Pathological platelets from patients with inherited disorders, presenting well-characterized and specific defects of either the platelet membrane (GT) or storage granules (GPS and HPS), have also been studied. The results obtained lead to the following conclusions: (1) the transducing system is normal in platelets unable to aggregate; (2) phosphorylation of P20 and P43 proteins can be complete with impaired release; and (3) when platelets lack alpha-granules the transducing system as well as the release of other granule populations are impaired. These results evidence the relationship between the absence of intraplatelet components and metabolic events.

Blood Platelet Disorders↗

PubMed2002

Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases.

Protein aggregation and the formation of highly insoluble amyloid structures is associated with a range of debilitating human conditions, which include Alzheimer's disease, Parkinson's disease, and the Creutzfeldt-Jakob disease. Muscle acylphosphatase (AcP) has already provided significant insights into mutational changes that modulate amyloid formation. In the present paper, we have used this system to investigate the effects of mutations that modify the charge state of a protein without affecting significantly the hydrophobicity or secondary structural propensities of the polypeptide chain. A highly significant inverse correlation was found to exist between the rates of aggregation of the protein variants under denaturing conditions and their overall net charge. This result indicates that aggregation is generally favored by mutations that bring the net charge of the protein closer to neutrality. In light of this finding, we have analyzed natural mutations associated with familial forms of amyloid diseases that involve alteration of the net charge of the proteins or protein fragments associated with the diseases. Sixteen mutations have been identified for which the mechanism of action that causes the pathological condition is not yet known or fully understood. Remarkably, 14 of these 16 mutations cause the net charge of the corresponding peptide or protein that converts into amyloid deposits to be reduced. This result suggests that charge has been a key parameter in molecular evolution to ensure the avoidance of protein aggregation and identifies reduction of the net charge as an important determinant in at least some forms of protein deposition diseases.

Alzheimer Disease↗

PubMed1995

[Demonstration of a specific profile of pathological Tau proteins in frontotemporal dementia cases].

We compared samples of different brain areas from patients with Alzheimer's disease (AD), progressive supranuclear palsy (PSP), controls subjects and from 4 patients who met the clinical and pathological criteria for frontotemporal dementia (FTD), using a Western blot analysis. We used polyclonal antibodies directed against Tau proteins and the monoclonal antibody AD2 for the immunodetection of the pathological Tau proteins which are the basic components of neurofibrillary degeneration. In the PSP and AD cases, we respectively detected the abnormal Tau proteins 64 and 69 and the Tau proteins 55, 64, and 69, systematically associated with bands and smears, corresponding to catabolic products or aggregates of these abnormal Tau proteins. In FTD cases, the abnormal Tau proteins 55, 64 and 69 were also detected in the frontal and temporal poles from the autopsied case and in the cortical biopsies. However, the profiles were different because smears and proteolytics products of Tau proteins were absent. There was no detection of abnormal Tau proteins in control brain homogenates and in biopsies from patients with other neurodegenerative disorders such as spongiform encephalopathies or primitive gliosis. These results demonstrate that pathological Tau proteins are produced during FTD degenerating process, despite the absence of neurofibrillary lesions.

Adult↗

PubMed2004

Effects of alpha-tocopherol on an animal model of tauopathies.

We have reported that transgenic (Tg) mice overexpressing human tau protein develop filamentous tau aggregates in the CNS. We overexpressed the smallest human tau isoform (T44) in the mouse CNS to model tauopathies. These tau Tg mice acquire age-dependent CNS pathologies, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Therefore, these Tg mice are a model that can be exploited for drug discovery in studies that target amelioration of tau-induced neurodegeneration as well as for elucidating mechanisms of tau pathology in various neurodegenerative tauopathies. Oxidative stress has been implicated in the pathogenesis of various neurodegenerative diseases, including tauopathies, and many epidemiological, clinical, and basic studies have suggested the neuroprotective effects of vitamin E in neurodegenerative diseases. To elucidate the role of oxidative damage in the pathological mechanisms of these Tg mice, we fed them alpha-tocopherol, the major component of antioxidant vitamin E. Supplementation of alpha-tocopherol suppressed and/or delayed the development of tau pathology, which correlated with improvement in the health and attenuation of motor weakness in the Tg mice. These results suggest that oxidative damage is involved in the pathological mechanisms of the tau Tg mice and that treatment with antioxidative agents like alpha-tocopherol may prevent neurodegenerative tauopathies.

Animals↗

PubMed1982

Multiple human serum binding of two thienopyridinic derivatives, ticlopidine and PCR 2362, and their distribution between HSA, alpha1-acid glycoprotein and lipoproteins.

The binding of two drugs, ticlopidine and PCR 2362, chemically related to thienopyridin, potent antiaggregant agents, was studied in vitro to serum and to the corresponding isolated proteins, HSA, alpha 1-AGP, VLDL, LDL and HDL, using equilibrium dialysis at pH 7.4 and 37 degrees. The binding of these drugs to HSA and lipoproteins was non-saturable. The binding capacity of the lipoproteins was much greater than that of HSA and appeared to be dependent on lipid content. The binding capacities of the apoproteins were less than 10% of that observed for the native lipoproteins suggesting that drug-lipoprotein binding involves drug solubilization in the lipid phase of lipoproteins rather than a classical binding to definite sites. However drug binding to alpha 1-AGP was saturable with n = 3 for both and K = 89,000 and 33,000 for ticlopidine and PCR 2362, respectively. At physiological concentration, alpha 1-AGP binding capacity represented 15% of total serum binding capacity which could double in pathological states, in which the level of this protein is increased.

Humans↗

PubMed2006

Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy.

In polyglutamine diseases such as X-linked spinobulbar muscular atrophy (SBMA), it is unknown whether the toxic form of the protein is an insoluble or soluble aggregate or a monomer. We have addressed this question by studying a full-length androgen receptor (AR) mouse model of SBMA. We used biochemistry and atomic force microscopy to immunopurify oligomers soluble after ultracentrifugation that are comprised of a single approximately 50-kDa N-terminal polyglutamine-containing AR fragment. AR oligomers appeared several weeks prior to symptom onset, were distinct and temporally dissociated from intranuclear inclusions, and disappeared rapidly after castration, which halts disease. This is the first demonstration of soluble AR oligomers in vivo and suggests that they underlie neurodegeneration in SBMA.

Aging↗

PubMed2006

A spectroscopic study of some of the peptidyl radicals formed following hydroxyl radical attack on beta-amyloid and alpha-synuclein.

There is clear evidence implicating oxidative stress in the pathology of many neurodegenerative diseases. Reactive oxygen species (ROS) are the primary mediators of oxidative stress, and hydrogen peroxide, a key ROS, is generated during aggregation of the amyloid proteins associated with some of these diseases. Hydrogen peroxide is catalytically converted to the aggressive hydroxyl radical in the presence of Fe(II) and Cu(I), which renders amyloidogenic proteins such as beta-amyloid and alpha-synuclein (implicated in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively) vulnerable to self-inflicted hydroxyl radical attack. Here, we report some of the peptide-derived radicals, detected by electron spin resonance spectroscopy employing sodium 3,5-dibromo-4-nitrosobenzenesulfonate as a spin-trap, following hydroxyl radical attack on Abeta(1-40), alpha-synuclein and some other related peptides. Significantly, we found that sufficient hydrogen peroxide was self-generated during the early stages of aggregation of Abeta(1-40) to produce detectable peptidyl radicals, on addition of Fe(II). Our results support the hypothesis that oxidative damage to Abeta (and surrounding molecules) in the brain in AD could be due, at least in part, to the self-generation of ROS. A similar mechanism could operate in PD and some other "protein conformational" disorders.

Alzheimer Disease↗

PubMed2006

Genotoxicity in Alzheimer's disease: role of amyloid.

Alzheimer's disease (AD) is a complex neurodegenerative disorder pathologically identified by the presence of extracellular senile plaques (SP) with a proteinaceous core composed of aggregates of the amyloid peptide (Abeta) and intracellular aggregates of the microtubule-associated protein tau (tau) as neurofibrillary tangles (NFTs). These hallmarks consist of abnormally folded proteinaceous components that are believed to be neurotoxic in AD. The mechanisms of toxicity remain unclear although oxidative stress and inflammation are implicated as mediators of the toxicity and these lesions, in turn, are known to damage cellular components including proteins, lipids in the membrane and DNA. However effects on genotoxicity and its role in AD are less clear. The present review discusses various influences, in particular of amyloid, on the genetic material and their possible role in the neurodegeneration in AD. Further, the amalgamation of genomics and proteomics in understanding AD and therapeutic development is suggested.

Alzheimer Disease↗

PubMed2004

Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway.

Cytoplasmic deposition of alpha-synuclein aggregates is a common pathological feature of many neurodegenerative diseases. Strong evidence for the causative role of alpha-synuclein in these disorders is provided by genetic linkage between this gene and familial Parkinson's disease and by neurodegeneration in transgenic animals that overexpress this protein. In particular, it has been hypothesized that the accumulation of nonfibrillar oligomers of alpha-synuclein, which serve as intermediates for fibrillar inclusion body formation, causes neurodegeneration. However, little is known about how cells handle potentially toxic protein aggregates. Here we demonstrate that cells are capable of clearing preformed alpha-synuclein aggregates via the lysosomal degradation pathway. Consequently, blocking this pathway causes the accumulation of the aggregates in non-neuronal cells, differentiated neuroblastoma cells, and primary cortical neurons. This aggregate clearance occurs in an aggregation stage-specific manner; oligomeric intermediates are susceptible to clearance, whereas mature fibrillar inclusion bodies are not. Neutralization of the acidic compartments leads to the accumulation of alpha-synuclein aggregates and exacerbates alpha-synuclein toxicity in postmitotic neuronal cells, suggesting that the accumulation of oligomeric intermediates may be an important event leading to alpha-synuclein-mediated cell death. These results suggest that enhancing lysosomal function may be a potential therapeutic strategy to halt or even prevent the pathogenesis of Parkinson's disease and other Lewy body diseases.

Animals↗

PubMed2001

Membrane binding and self-association of alpha-synucleins.

Although its function is unknown, alpha-synuclein is widely distributed in neural tissue and is the major component in the pathological aggregates found in patients with Parkinson's disease, Alzheimer's disease, Down's syndrome, and multiple system atrophy. In this report, we have quantified the binding alpha-synucleins to lipid membranes. In contrast to previous studies, we find, using real time equilibrium fluorescence methods, that alpha-synuclein binds strongly to large, unilamellar vesicles with either anionic or zwitterionic headgroups. Membrane binding is also strong for beta-synuclein, phosphorylated alpha-synuclein, and a synuclein mutant that is associated with familial Parkinson's disease. In solution at less than 400 nM, synuclein has a tendency to undergo concentration-dependent oligomerization as determined by changes in intrinsic fluorescence and fluorescence resonance energy transfer. Above this concentration, the protein begins to aggregate into structures visible by light scattering. Although membrane binding does not affect the secondary structure of alpha-synuclein, it greatly inhibits the ability of this protein to self-associate. Taken together, our results indicate that pathological conditions may be associated with a disruption in synuclein-membrane interactions.

Blotting, Western↗

PubMed1996

Preservation of native conformation during aluminium-induced aggregation of tau protein.

Aluminium exposure has been shown to result in aggregation of microtubule-associated protein tau in vitro. In the light of recent observations that the native random structure of tau protein is maintained in its monomeric and dimeric states as well as in the paired helical filaments characteristic of Alzheimer's disease, it is likely that factors playing a causative role in neurofibrillary pathology would not drastically alter the native conformation of tau protein. We have studied the interaction of tau protein with aluminium using circular dichroism (CD) and 27Al NMR spectroscopy. The CD studies revealed a five-fold increase in the observed elipticity of the tau-aluminium assembly. The increase in elipticity was not associated with a change in the general conformation of the protein and was most likely due to an aggregation of the tau protein induced by aluminium. 27Al NMR spectroscopy confirmed the binding of aluminium to tau protein. Hyperphosphorylation of tau in Alzheimer's disease is known to be associated with defective microtubule assembly in this condition. Abnormally phosphorylated tau exists in a polymerized form in the paired helical filaments (PHF) which constitute the neurofibrillary tangles found in Alzheimer's disease. While it is hypothesized that its altered biophysical characteristics render abnormally phosphorylated tau resistant to proteolysis, causing the formation of stable deposits, the sequence of events resulting in the polymerization of tau are little understood, as are the additional factors or modifications required for this process. Based on the results of our spectroscopic studies, a model for the sequence of events occurring in neurofibrillary pathology is proposed.

Aluminum↗

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↗