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Results for “Protein Aggregation, Pathological”

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PubMed2000

The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity.

Parkinson's disease (PD) is the most common motor disorder affecting the elderly. PD is characterized by the formation of Lewy bodies and death of dopaminergic neurons. The mechanisms underlying PD are unknown, but the discoveries that mutations in alpha-synuclein can cause familial PD and that alpha-synuclein accumulates in Lewy bodies suggest that alpha-synuclein participates in the pathophysiology of PD. Using human BE-M17 neuroblastoma cells overexpressing wild-type, A53T, or A30P alpha-synuclein, we now show that iron and free radical generators, such as dopamine or hydrogen peroxide, stimulate the production of intracellular aggregates that contain alpha-synuclein and ubiquitin. The aggregates can be identified by immunocytochemistry, electron microscopy, or the histochemical stain thioflavine S. The amount of aggregation occurring in the cells is dependent on the amount of alpha-synuclein expressed and the type of alpha-synuclein expressed, with the amount of alpha-synuclein aggregation following a rank order of A53T > A30P > wild-type > untransfected. In addition to stimulating aggregate formation, alpha-synuclein also appears to induce toxicity. BE-M17 neuroblastoma cells overexpressing alpha-synuclein show up to a fourfold increase in vulnerability to toxicity induced by iron. The vulnerability follows the same rank order as for aggregation. These data raise the possibility that alpha-synuclein acts in concert with iron and dopamine to induce formation of Lewy body pathology in PD and cell death in PD.

Benzothiazoles↗

PubMed1994

An autoantibody directed against human thrombin anion-binding exosite in a patient with arterial thrombosis: effects on platelets, endothelial cells, and protein C activation.

An autoantibody, developed by a patient with severe and recurrent arterial thrombosis, was characterized to be directed against the anion-binding exosite of thrombin, and inhibited all thrombin interactions requiring this secondary binding site without interfering with the catalytic site. The effect of the antibody was studied on thrombin interactions with platelets and endothelial cells from human umbilical veins (HUVEC). The autoantibody specifically and concentration-dependently inhibited alpha-thrombin-induced platelet activation and prostacyclin (PGI2) synthesis from HUVEC. It had no effect when gamma-thrombin or the thrombin receptor activation peptide SFLLR were the inducers. The effect of the antibody on protein C activation has been studied. The antibody blocked the thrombin-thrombomodulin activation of protein C. The inhibition of the activation was maximal with a low concentration of thrombomodulin. The fact that the autoantibody inhibited concentration-dependent alpha-thrombin-induced platelet and endothelial cell functions emphasizes the crucial role of the anion-binding exosite of thrombin to activate its receptor. In regard to the pathology, the antibody inhibited two vascular processes implicated in thrombin-antithrombotic functions, PGI2 secretion, and protein C activation, which could be implicated in this arterial thrombotic disease.

Anions↗

PubMed2004

Huntingtin and its role in neuronal degeneration.

Huntington's disease results from a polyglutamine expansion in the N-terminal region of huntingtin (htt). This abnormality causes protein aggregation and leads to neurotoxicity. Despite its widespread expression in the brain and body, mutant htt causes selective neurodegeneration in Huntington's disease patient brains. However, Huntington's disease mouse models expressing mutant htt do not have obvious neurodegeneration despite significant neurological symptoms. Most Huntington's disease mouse models display the accumulation of toxic N-terminal mutant htt fragments in both the nucleus and neuronal processes, suggesting that these subcellular sites are hotspots for the early neuropathology of Huntington's disease. Intranuclear htt affects gene expression and may cause neuronal dysfunction. Mutant htt in neuronal processes affects axonal transport and induces degeneration, and these effects may be more relevant to the selective neurodegeneration in Huntington's disease. Growing evidence has also suggested that mutant htt mediates multiple pathological pathways. This review discusses the early pathological changes identified in Huntington's disease cellular and animal models. These changes may be the causes of neurode-generation.

Animals↗

PubMed2003

Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: a potential mechanism for loss of huntingtin function in Huntington's disease.

Aggregation of huntingtin (htt) in neuronal inclusions is associated with the development of Huntington's disease (HD). Previously, we have shown that mutant htt fragments with polyglutamine (polyQ) tracts in the pathological range (>37 glutamines) form SDS-resistant aggregates with a fibrillar morphology, whereas wild-type htt fragments with normal polyQ domains do not aggregate. In this study we have investigated the co-aggregation of mutant and wild-type htt fragments. We found that mutant htt promotes the aggregation of wild-type htt, causing the formation of SDS-resistant co-aggregates with a fibrillar morphology. Conversely, mutant htt does not promote the fibrillogenesis of the polyQ-containing protein NOCT3 or the polyQ-binding protein PQBP1, although these proteins are recruited into inclusions containing mutant htt aggregates in mammalian cells. The formation of mixed htt fibrils is a highly selective process that not only depends on polyQ tract length but also on the surrounding amino acid sequence. Our data suggest that mutant and wild-type htt fragments may also co-aggregate in neurons of HD patients and that a loss of wild-type htt function may contribute to HD pathogenesis.

Animals↗

PubMed2003

Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective.

Lewy bodies (LBs), which are the hallmark pathologic features of Parkinson's disease and of dementia with LBs, have several morphologic and molecular similarities to aggresomes. Whether such cytoplasmic inclusions contribute to neuronal death or protect cells from the toxic effects of misfolded proteins remains controversial. In this report, the role of aggresomes in cell viability was addressed in the context of over-expressing alpha-synuclein and its interacting partner synphilin-1 using engineered 293T cells. Inhibition of proteasome activity elicited the formation of juxtanuclear aggregates with characteristics of aggresomes including immunoreactivity for vimentin, gamma-tubulin, ubiquitin, proteasome subunit, and hsp70. As expected from the properties of aggresomes, the microtubule disrupting agents, vinblastin and nocodazole, markedly prevented the formation of these inclusions. Similar to LBs, the phosphorylated form of alpha-synuclein co-localized in these synphilin-1-containing aggresomes. Although the caspase inhibitor z-VAD-fmk significantly reduced the number of apoptotic cells, it had no impact on the percentage of aggresome-positive cells. Finally, quantitative analysis revealed aggresomes in 60% of nonapoptotic cells but only in 10% of apoptotic cells. Additionally, alpha-synuclein-induced apoptosis was not coupled with increased prevalence of aggresome-bearing cells. Taken together, these observations indicate a disconnection between aggresome formation and apoptosis, and support a protective role for these inclusions from the toxicity associated with the combined over-expression of alpha-synuclein and synphilin-1.

Amino Acid Chloromethyl Ketones↗

PubMed2006

Biochemical staging of synucleinopathy and amyloid deposition in dementia with Lewy bodies.

The primary feature of dementia with Lewy bodies (DLB) is the aggregation of alpha-synuclein into characteristic lesions: Lewy bodies (LBs) and Lewy neurites. However, in most of DLB cases, LBs are associated with neurofibrillary tangles and amyloid plaques (both Alzheimer disease [AD]-related lesions). We wanted to determine if this overlap of lesions is statistical, as a result of the late onset of both diseases, or results from a specific physiopathological synergy between synucleinopathy and either tauopathy or amyloid pathology. All patients with DLB from our prospective and multidisciplinary study were analyzed. These cases were compared with cases with pure AD and patients with Parkinson disease and controls. All cases were analyzed thoroughly at the neuropathologic and biochemical levels with a biochemical staging of aggregated alpha-synuclein, tau, and Abeta species. All sporadic cases of DLB were associated with abundant deposits of Abeta x-42 that were similar in quality and quantity to those of AD. Amyloid precursor protein (APP) dysfunction is a risk factor for AD as demonstrated by pathogenic mutations and Abeta accumulation. The constant and abundant Abeta x-42 deposition in sporadic DLB suggests that synucleinopathy is also promoted by APP dysfunction. Therefore, we conclude that APP is a therapeutic target for both AD and DLB.

Aged↗

PubMed2006

Peptide model systems for amyloid fiber formation: design strategies and validation methods.

The rational understanding of the factors involved in the formation of amyloid deposits in tissue is fundamental to the identification of novel therapeutic strategies to prevent or cure pathological conditions such as Alzheimer's and Parkinson's disease or spongiform encephalopathies. Given the complexity of the molecular events driving protein self-association, a frequent strategy in the field has consisted of designing simplified model systems that facilitate the analysis of the elements that predispose polypeptides toward amyloid formation. In fact, these systems have provided very valuable knowledge on the determinants underlying structural transitions to the polymeric beta-sheet state present in amyloid fibers and more disordered aggregates. In this chapter, we will describe different approaches to obtain and design model systems for amyloidogenesis, as well as the methodologies that are typically used to validate them. We will also show how some of the general principles obtained from these studies can be applied for de novo design purposes and for the sequence-based identification of amyloidogenic stretches in proteins.

Alzheimer Disease↗

PubMed2002

Carnosine and related dipeptides protect human ceruloplasmin against peroxyl radical-mediated modification.

Ceruloplasmin (CP) is the major plasma antioxidant and copper transport protein. In a previous study, we showed that the aggregation of human ceruloplasmin was induced by peroxyl radicals. We investigated the effects of antioxidant dipeptides carnosine, homocarnosine and anserine on peroxyl radical-mediated ceruloplasmin modification. Carnosine, homocarnosine and anserine significantly inhibited the aggregation of CP induced by peroxyl radicals. When CP was incubated with peroxyl radicals in the presence of three compounds, ferroxidase activity, as measured by the activity staining method, was protected. All three compounds also inhibited the formation of dityrosine in peroxyl radicals-treated CP. The results suggest that carnosine and related compounds act as peroxyl radical scavenger to protect the protein modification. It is proposed that carnosine and related peptides might be explored as potential therapeutic agents for pathologies that involve CP modification mediated by peroxyl radicals generated in the lipid peroxidation.

Anserine↗

PubMed2002

HSP20, low-molecular-weight heat shock-related protein, acts extracellularly as a regulator of platelet functions: a novel defense mechanism.

We previously showed that a dissociated form of a low-molecular-weight heat shock-related protein 20 (HSP20) but not an aggregated form of HSP20 suppresses platelet aggregation. In the present study, we investigated the behavior of HSP20 in response to endothelial injury and the possible mechanism of HSP20 in platelet functions. The levels of HSP20 in vessel wall after endothelial injury were markedly reduced. This observation was supported by the results of Western blotting analysis and immunohistochemical analysis. Additionally, the plasma levels of HSP20 in cardiomyopathic hamsters were markedly elevated. Centrifugation on sucrose density gradients allowed detection mainly of the dissociated form of plasma HSP20 in these hamsters. Human platelets showed specific binding sites for HSP20. Moreover, HSP20 markedly reduced thrombin-induced phosphoinositide hydrolysis by phospholipase C in human platelets. Taken together, our results strongly suggest that HSP20, which immediately responds to pathological events, acts extracellularly as a regulator of platelet functions.

Animals↗

PubMed2005

Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways.

The expansion of CAG repeats encoding glutamine (polyQ) causes, to date, 9 late-onset progressive neurodegenerative disorders, including Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxias 1, 2, 3, 6, 7, and 17. Although many studies using both knockout and transgenic mouse models suggest that a toxic gain of function is central to neuronal dysfunction, the exact mechanisms of neurotoxic effects remain elusive. Protein aggregations within neurons seem to be a common manifestation in almost all polyQ diseases, and such accumulations are perhaps major triggers of cellular stress and neuronal death. Recent data lead to the tantalizing proposal that disruption of axonal transport pathways within long, narrow-caliber axons could lead to protein accumulations that can elicit neuronal death, ultimately causing a neuronal dysfunction pathway observed in polyQ expanded diseases. Perhaps perturbations in transport pathways are an early event involved in instigating polyQ disease pathology.

Animals↗

PubMed2004

The role of thrombospondin-1 in human disease.

Thrombospondin-1 (TSP-1) is a large matricellular glycoprotein secreted by many cell types. It is a component of the extracellular matrix during active and subacute processes. Due to TSP-1's ability to interact with a variety of matrix proteins and cell-surface receptors, controversy exists about its conflicting functions. In this review, we will discuss the role of TSP-1 in human disease.

Disease↗

PubMed1999

Mucosal infection and vaccination against feline immunodeficiency virus.

Feline immunodeficiency virus (FIV) infection is a naturally occurring lentiviral infection of cats which progresses to immunodeficiency in a manner strikingly similar to that observed in HIV infection in man. The rectal and cervico-vaginal mucosae are common routes of transmission of HIV and it has been shown that the gastrointestinal tract is an important site of HIV infection and primary pathology. Although biting is the principle mode of transmission for FIV, we have shown that it is possible to reliably infect cats via both the rectal and vaginal routes. Using a biotin-streptavidin linked immunoperoxidase technique we have detected FIV core and envelope proteins in the colonic follicle associated epithelial cells, cells within the lymphoid follice and occasional cells in the lamina propria. Further, in the intestine we have detected FIV RNA and proviral DNA in epithelial cells, colonic lymphoid aggregates and isolated lamina propria cells. We have studied a group of asymptotic cats which have been rectally infected with FIV for 1 year or longer and shown an increase in the number of lamina propria CD8+ cells and greater levels of IL-2, IL-6, IL-10 and gamma-IFN mRNA. Since these cats remained clinically healthy these results might suggest that both local antibody and class I restricted cytotoxic lymphocytes (CTLs) may play a role in control of viral replication. We have investigated a range of vaccination regimes for their ability to generate responses which would protect from rectal challenge with virulent virus. Cats have been immunized with whole virus (FIV-pet, FIV-GLA-8), V3, V3MAP or C2 with cholera toxin (CT), or Quil A based adjuvants via rectal, intra-nasal, parenteral or targeted lymph node routes, and challenged rectally with ten mucosal cat infectious doses (MCID) of FIV-GLA-8. We have shown that the adjuvant effects of cholera toxin and Quil A are not influenced by the route of delivery (intraperitoneal (i.p.) versus rectal) with CT more effective in stimulating humoral and Quil A more effective in stimulating cellular responses to FIV antigens. However we have shown that, quantitatively, CT is more effective when used as an adjuvant via the intra-nasal than the rectal route. Recently, we have begun to investigate if the promising results obtained with targeted lymph node (TLN) vaccination in monkeys could be reproduced in the cat. We have shown that TLN was more effective than rectal immunisation in stimulating both humoral and proliferative responses. In a preliminary study we have also been able to detect FIV specific CTLs and have observed protection from rectal challenge in four out of four cats.

Animals↗

PubMed2003

Lysophosphatidic acid is the unique platelet-activating substance in human malignant ascites.

Pathological blood platelet activation promotes thrombosis in cancer patients, but the specific substances involved are still under investigation. Tumor exudates have been described to contain lysophosphatidic acid (LPA), a known platelet-activating substance, and the concentration of mediators present in malignant ascites are constantly equilibrated with the concentration in plasma. We hypothesized that the ascites of cancer patients might activate platelets, and that this may be caused by LPA. Indeed, ascites samples from 15 different patients with cancer induced shape change and an increase of cytosolic Ca2+ of isolated platelets; both responses were cross-desensitized by lysophosphatidic acid (LPA), but not by other platelet stimuli. Moreover shape change, Ca2+ mobilization and aggregation induced by ascites could be completely blocked by pretreatment of platelets with specific LPA-receptor antagonists. Phospholipids were extracted from ascites, separated by thin layer chromatography, and individual fractions were tested for activity on platelets. The platelet activating substance co-migrated with LPA, whereas other fractions were inactive. Notably, ascites induced through LPA-receptor activation platelet aggregation in whole blood. Our results suggest that LPA plays an essential role in the pathological platelet activation in cancer patients. We propose that LPA receptor antagonists could be effective in blocking cancer-associated platelet activation and thus preventing thrombosis.

Ascites↗

PubMed1983

[The adenylate cyclase system of human platelets].

This review summarizes current knowledge on the adenylate cyclase system of human platelets. In the first part, the main molecular entities of this system are described, emphasis being layed on coupling proteins (Ns, Ni) which transduce the hormonal message from receptors to the catalytic unit. The mechanisms by which regulation of adenylate cyclase occurs is discussed and a comprehensive model is proposed. In the second part, are reviewed the hormonal and non hormonal regulators of the adenylate cyclase system. The role of the platelet adenylate cyclase system is discussed in relation to pathology and the action of certain drugs on platelet activity.

Adenosine↗

PubMed1990

Human growth hormone association and binding study in vitro: high performance size exclusion chromatography and radioimmunoassay-measured levels in plasma of normal and acromegalic subjects.

Human growth hormone (hGH), like other protein hormones, consists of several molecular forms both in the pituitary and in plasma. In recent years carrier proteins have been detected and studied for growth hormone, using different experimental approaches. In the present study we have attempted to investigate whether hGH could be separated and identified in molecular or aggregated forms using high performance size exclusion chromatography and a small plasma sample, without particular treatment, in order to investigate specific hGH-binding proteins in normal as well as in acromegalic subjects. Results showed that it was possible to observe binding or/and the formation of a complex between free hormone and other molecules that could be specific binding proteins. Equilibrium was reached in a few minutes (7-10 min) and was reversible, as observed with labelled hormone using low and high concentrations of hGH in the incubation medium. At 37 degrees C the associated form at equilibrium was 30% of the total (measured as percent of total radioactivity with labelled hormone) in a plasma medium in which the original growth hormone was absent. Acromegalic plasma demonstrated that the percent of the associated form (namely the 80-kDa form) was less than that in normal humans. This may be due to the fact that capacity binding and competition between labelled and non-labelled growth hormone were favorable to the non-labelled form, if only for the high concentrations in this type of pathology. Therefore our results seem to be in agreement with the hypothesis that acromegalic subjects do not lack this aggregation capacity.

Acromegaly↗

PubMed1996

Interferon-gamma-producing T cells in giant cell vasculitis represent a minority of tissue-infiltrating cells and are located distant from the site of pathology.

Giant cell vasculitis is an arteritis that predominantly affects medium- and large-sized arteries. Genetic risk factors and clonal expansion of selected CD4+ T cell specificities in the vascular lesions support the model that giant cell arteritis is a T-cell-driven disease. Interferon (IFN)-gamma production in the tissue is intimately associated with the formation of the inflammatory infiltrates. Antigens inducing stimulation of T cells are unknown. To provide indirect evidence for the type and the tissue localization of the antigen, we examined CD4+ T cells in the lesions that secrete IFN-gamma. Temporal artery specimens from patients with giant cell arteritis were analyzed bu two-color immunohistochemistry applying antibodies to T cell markers. IFN-gamma, the interleukin-2 receptor alpha-chain (CD25) and talin, a cytoskeletal protein that is reorganized in T cells interacting with antigen-presenting cells. Proliferating cells in the lesions were identified through the expression of the Ki-67 nuclear antigen. More than 90% of tissue-infiltrating IFN-gamma-producing cells were CD4+ CD45RO+. They represented a minute subset (2 to 4%) of tissue-infiltrating T cells. IFN-gamma+ T cells aggregated in the adventitial layer of the inflamed artery where they were either diffusely distributed or arranged in clusters. The majority of IFN-gamma-secreting T cells expressed CD25. IFN-gamma+ T cells included a fraction of cells that had reorganized the cytoskeletal protein talin, indicating an interaction of the T cell receptor and an antigen-presenting cell. A subset of IFN-gamma-expressing T cells was undergoing proliferation in the tissue. IFN-gamma-producing T cells in vasculitic lesions of giant cell arteritis express several markers that identify them as T cells that have recently been stimulated through their antigen-specific receptor. These putatively disease-relevant T cells represent only a very minor fraction of tissue-infiltrating cells. Their preferential accumulation in the adventitia is most compatible with the model that they contact the relevant antigen primarily in this particular region of the artery. Their regulatory function appears to extend into the inner media and intima where pathological changes in giant cell arteritis are most pronounced.

Arteritis↗

PubMed2005

Molecular pathology and pathogenesis of inclusion-body myositis.

We summarize the molecular phenotype, diagnostic criteria, and the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis (s-IBM), a muscle disease usually of persons over age 50. On the basis of our research, several processes seem to be important in relation to the still-speculative pathogenesis: 1) increased transcription and accumulation of amyloid-beta precursor protein (AbetaPP), and accumulation of its proteolytic fragment Abeta; 2) abnormal accumulation of cholesterol, caveolin-1, and apolipoprotein E; 3) oxidative stress; 4) accumulations of intramuscle fiber multiprotein aggregates; and 5) evidence that unfolded/misfolded proteins participate in s-IBM pathogenesis. Our basic hypothesis is that overexpression of AbetaPP within the aging muscle fibers is an early upstream event causing a subsequent pathogenic cascade.

Aging↗

PubMed2004

Microtubule-associated protein tau gene: a risk factor in human neurodegenerative diseases.

Tau is a microtubule-associated protein mainly expressed in neurons of central nervous system, which is crucial in the maintenance of these cells. It has a central role in the polymerization and stabilization of microtubules and in the traffic of organelles along axons and dendrites. Aggregates of hyperphosphorylated forms of tau protein participate in the formation of neurofibrillary tangles, which characterize numerous neurodegenerative disorders named tauopathies. The analysis of tau gene and the study of familial cases of tauopathies have led to the discovery of tau gene mutations that cause inherited dementia designated as Frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17). However, these familial cases remain rare compared to the sporadic tauopathies, the later involving both genetic and environmental etiologic factors. As tau pathology represents a primary pathogenic event in various neurodegenerative diseases, the hypothesis that tau genotype could influence the development of these diseases was tested by several groups. This review summarizes advances in the molecular genetics of the tau gene, as well as recent studies addressing the disease incidence of novel tau polymorphisms in different neurodegenerative diseases. Hopefully, the identification of several genetic defects of the tau gene will be helpful in improving our understanding of the role of tau protein in the pathogenesis of various neurodegenerative diseases.

Base Sequence↗