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Results for “Protein Aggregation, Pathological”

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PubMed1995

[Expression of bc1-2 protein in collagen vascular diseases with pulmonary interstitial involvement].

Expression of bc1-2 protein was studied immunohistochemically in 25 patients with collagen vascular diseases and in 10 patients with idiopathic interstitial pneumonia. The collagen vascular diseases included rheumatoid arthritis (n = 9), progressive systemic sclerosis (n = 9), polymyositis/dermatomyositis (n = 4), Sjögren's syndrome (n = 2), and systemic lupus erythematosus (n = 1). All 35 patients underwent open lung biopsy; cellular infiltration, fibrosis, and lymphoid aggregation were scored according to Cherniack's classification. T lymphocytes (CD43: DFT-1) and B lymphocytes (CD20:L-26) were also evaluated. Expression of bc1-2 protein was dominant in T lymphocytes infiltrating the alveolar interstitium and in B lymphocytes in the mantle zone of lymphoid follicles. In collagen vascular diseases, the degree of expression of bc1-2 protein in those T lymphocytes was closely related to the alveolar lymphocyte infiltration score. However, these findings were not marked in the patients with idiopathic interstitial pneumonia, and were not related to the underlying disease in the patients with collagen vascular diseases. The expression of bc1-2 protein in T lymphocytes was not related to fibrosis or to lymphoid aggregation. Expression of bc1-2 protein in B lymphocytes did not correlate with pathological scores or with underlying disease. Bc1-2 protein has been recognized as an oncogene that suppresses apoptosis. Marked expression of bc1-2 protein in T lymphocytes from patients with collagen vascular diseases indicates that oversuppression of apoptosis may be related to the pathogenesis of pulmonary interstitial involvement in these conditions. Further clinicopathological studies focusing on apoptosis in collagen vascular diseases and in idiopathic interstitial pneumonia are needed.

Apoptosis↗

PubMed2005

A novel therapeutic strategy for polyglutamine diseases by stabilizing aggregation-prone proteins with small molecules.

Polyglutamine diseases, such as Huntington disease (HD) and spinocerebellar ataxia 1 and 3, are autosomal dominant neurodegenerative disorders. They are caused by CAG trinucleotide repeat expansions that are translated into abnormally long polyglutamine tracts. One of the pathological hallmarks in polyglutamine diseases is the formation of intranuclear inclusions of polyglutamine-containing proteins in the brain. Although causal relationships between polyglutamine aggregation and cellular toxicity are much debated, inhibition of the polyglutamine-mediated protein aggregation may provide treatment options for polyglutamine diseases. However, the extreme insolubility of expanded polyglutamines makes it difficult to prepare polyglutamine-containing proteins on a large scale and to search for aggregation inhibitors by in vitro high-throughput screening. To overcome this we developed a novel in vitro model system for polyglutamine diseases using myoglobin as a host protein. We searched for small molecules that inhibit polyglutamine-mediated aggregation by in vitro screening with a mutant myoglobin containing a 35 polyglutamine repeat. The screening assay revealed that disaccharides have a potential to inhibit polyglutamine-induced protein aggregation and to increase survival in a cellular model of HD. Oral administration of trehalose, the most effective disaccharide in vitro, decreased polyglutamine aggregates in the cerebrum and liver, improved motor dysfunction and extended life span in a transgenic mouse model of HD. In vitro experiments suggest that the beneficial effects of trehalose result from its ability to bind and stabilize polyglutamine-containing proteins. The lack of toxicity and high solubility, coupled with its efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The stabilization of aggregation-prone proteins with small molecules is an attractive strategy because it can block the initial stage of the disease cascade. In addition, this therapeutic approach could be applied not only to polyglutamine diseases but also to a wide variety of misfolding-induced diseases.

Amyloid↗

PubMed1978

Tamm-Horsfall protein in the glomerular capsular space.

Tamm-Horsfall protein was detected within the capsular space by immunofluorescence in 7 of 72 consecutive patients on whom renal immunopathological studies were performed. Three patients showed prominent aggregates or crescentic collections affecting 30-50% glomeruli; the remaining four patients showed smaller aggregates between lobules. All patients showed pathological evidence of tubulointerstitial disease. It is suggested that Tamm-Horsfall protein in the capsular space is a sign of intratubular urinary backflow and that Tamm-Horsfall antiserum is a useful addition to the reagents used in the immunofluorescence study of renal biopsies.

Adult↗

PubMed2002

The cell biology of alpha-synuclein: a sticky problem?

Parkinson's disease (PD) is the most common neurodegenerative motor disorder, marked by chronic progressive loss of neurons in the substantia nigra, thereby damaging purposeful control of movement. For decades, it was believed that PD was caused solely by environmental causes. However, the discovery of genetic factors involved in PD has revolutionized our attempts to understand the disease's pathology. PD now appears to be more polygenetic than previously thought and is most likely caused by a complex interaction of genetic risks and environmental exposures. The first gene found to be mutated in PD encodes for the presynaptic protein alpha-synuclein, which is also a major component of Lewy bodies and Lewy neurites, the neuropathological hallmarks of the disease. While these findings provide a classic example of how rare genetic mutations in disease can point to important pathways in idiopathic disease pathologies, much of the study of alpha-synuclein has focused on understanding how this protein undergoes the transition from an unfolded monomer to amorphous aggregates or Lewy body-like filaments rather than addressing what its fundamental function might be. Since alterations in synuclein function may predispose to the disease pathology of PD, regardless of the presence of genetic mutations, a more thorough understanding of the cellular regulation and function of alpha-synuclein may be of crucial importance to our understanding of this degenerating disorder.

Humans↗

PubMed2002

Role of glycosylation in hyperphosphorylation of tau in Alzheimer's disease.

In Alzheimer's disease (AD) brain, microtubule-associated protein tau is abnormally modified by hyperphosphorylation and glycosylation, and is aggregated as neurofibrillary tangles of paired helical filaments. To investigate the role of tau glycosylation in neurofibrillary pathology, we isolated various pools of tau protein from AD brain which represent different stages of tau pathology. We found that the non-hyperphosphorylated tau from AD brain but not normal brain tau was glycosylated. Monosaccharide composition analyses and specific lectin blots suggested that the tau in AD brain was glycosylated mainly through N-linkage. In vitro phosphorylation indicated that the glycosylated tau was a better substrate for cAMP-dependent protein kinase than the deglycosylated tau. These results suggest that the glycosylation of tau is an early abnormality that can facilitate the subsequent abnormal hyperphosphorylation of tau in AD brain.

Acetylglucosamine↗

PubMed2005

Effect of resveratrol on angiogenesis and platelet/fibrin-accelerated tumor growth in the chick chorioallantoic membrane model.

We carried out this investigation to examine the effects on angiogenesis-mediated processes and to define anti-angiogenesis mechanisms for flavonoids. We examined the effects and mechanisms of the flavonoid resveratrol on angiogenesis and tumor growth using the chick chorioallantoic membrane (CAM) model of angiogenesis, the CAM tumor growth model, and the effect on p53 in fibroblast growth factor-2 (FGF2) stimulated human endothelial cells using immunoassay. Resveratrol demonstrated potent inhibition (effective dose50=0.7+/-0.1 microM) of FGF2-induced angiogenesis and tumor growth. Furthermore, resveratrol significantly (P<0.01) inhibited platelet/fibrin clot-promoted human colon and fibrosarcoma tumor growth in the CAM tumor model. Resveratrol in a concentration-dependent (1-3 microM) manner significantly promoted apoptosis in FGF2-stimulated endothelial cells by increasing p53 protein production. These data indicated potent anti-angiogenesis efficacy, inhibition of tumor growth, and clot-mediated enhanced tumor growth. These data suggest potential anticancer benefits as a chemopreventive and chemotherapeutic for the flavonoid resveratrol.

Angiogenesis Inhibitors↗

PubMed2001

Inefficient processing of an olfactomedin-deficient myocilin mutant: potential physiological relevance to glaucoma.

Mutations in TIGR/MYOC (myocilin), a secretory protein of unknown function, have been recently linked to glaucoma. Most known mutations map to the C-terminus, an olfactomedin-like domain. We have previously shown that, in contrast to the wild-type, a truncated form of myocilin lacking the olfactomedin domain is not secreted. In this study, we present evidence that the mutant protein is not correctly processed in the endoplasmic reticulum (ER) and accumulates into insoluble aggregates. In addition, we show that the presence of increasing amounts of mutant protein induces a fraction of the soluble, native myocilin to move to the insoluble fraction. Given the importance of such protein aggregates in the etiology of several aging-related diseases, we propose that olfactomedin-defective mutants might contribute to the pathology of glaucoma through a mechanism involving intracellular accumulation of misfolded proteins.

Adenoviridae↗

PubMed2005

Neuroprotection by iron chelator against proteasome inhibitor-induced nigral degeneration.

The cause of the neurodegenerative process in Parkinson's disease (PD) remains unclear, but evidence suggests that failure of the ubiquitin-proteasome system may play a major role in the pathogenesis of the disease. Iron is believed to be a key contributor to PD pathology by inducing aggregation of alpha-synuclein and by generating oxidative stress. Our present studies have shown that micro-injection of the proteasome inhibitor lactacystin into the substantia nigra (SN) of C57BL/6 mice causes significant loss of dopaminergic cells and induces intracellular inclusion body formation. We have also found that co-injection of the iron chelator desferrioxamine not only attenuates the lactacystin-induced dopamine neuron loss, but also reduces the presence of ubiquitin-positive intracellular inclusions in the SN, whereas use of iron-deficient diet has no such protective effects. These results may support that iron plays a key role in proteasome inhibitor-induced nigral pathology and that reducing iron reactivity may prevent dopaminergic neuron degeneration and reduce abnormal protein aggregation.

Acetylcysteine↗

PubMed2006

Amyloids, prions and the inherent infectious nature of misfolded protein aggregates.

Misfolded aggregates present in amyloid fibrils are associated with various diseases known as "protein misfolding" disorders. Among them, prion diseases are unique in that the pathology can be transmitted by an infectious process involving an unprecedented agent known as a "prion". Prions are infectious proteins that can transmit biological information by propagating protein misfolding and aggregation. The molecular mechanism of prion conversion has a striking resemblance to the process of amyloid formation, suggesting that misfolded aggregates have an inherent ability to be transmissible. Intriguing recent data suggest that other protein misfolding disorders might also be transmitted by a prion-like infectious process.

Alzheimer Disease↗

PubMed2001

Glucocorticoid modulation of androgen receptor nuclear aggregation and cellular toxicity is associated with distinct forms of soluble expanded polyglutamine protein.

Spinobulbar muscular atrophy is a progressive motor neuron disease caused by abnormal polyglutamine tract expansion in the androgen receptor (AR) gene, and is part of a family of central nervous system (CNS) neurodegenerative diseases, including Huntington's disease (HD). Each pathologic protein is widely expressed, but the cause of neuronal degeneration within the CNS remains unknown. Many reports now link abnormal polyglutamine protein aggregation to pathogenesis. A previous study reported that activation of the wild-type glucocorticoid receptor (wtGR) suppressed the aggregation of expanded polyglutamine proteins derived from AR and huntingtin, whereas a mutant receptor containing an internal deletion, GRDelta108-317, increased polyglutamine protein aggregation, in this case primarily within the nucleus. In this study, we use these two forms of GR to study expanded polyglutamine AR protein in different cell contexts. Using cell biology and biochemical approaches, we find that wtGR promotes soluble forms of the protein and prevents nuclear aggregation in NIH3T3 cells and cultured neurons. In contrast, GRDelta108-317 decreases polyglutamine protein solubility, and causes formation of nuclear aggregates in non-neuronal cells. Nuclear aggregates recruit hsp72 more rapidly than cytoplasmic aggregates, and are associated with decreased cell viability. Limited proteolysis and chemical cross-linking suggest unique soluble forms of the expanded AR protein underlie these distinct biological activities. These observations provide an experimental framework to understand why expanded polyglutamine proteins may be toxic only to certain populations of cells, and suggest that unique protein associations or conformations of expanded polyglutamine proteins may determine subsequent cellular effects such as nuclear localization and cellular toxicity.

3T3 Cells↗

PubMed2006

Linker histone H1 binds to disease associated amyloid-like fibrils.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative diseases of the central nervous system. These two diseases share a common feature in that a normally soluble peptide (amyloid-beta) or protein (alpha-synuclein) aggregates into an ordered fibrillar structure. As well as structural similarities observed between fibrillar aggregates related to these diseases, common pathological processes of increased oxidative injury, excitotoxicity and altered cell cycle are also evident. It was the aim of this study to identify novel interacting proteins to the amyloid-like motif and therefore identify common potential pathways between neurodegenerative diseases that share biophysical properties common to classical amyloid fibrils. Optimal ageing of recombinant proteins to form amyloid-like fibrils was determined by electron microscopy, Congo red birefringement and photo-induced cross-linking. Using pull-down assays the strongest detected interacting protein to the amyloid-like motifs of amyloid-beta, alpha-synuclein and lysozyme was identified as histone H1. The interaction with the amyloid-like motif was confirmed by techniques including surface plasmon resonance and immunohistochemistry. Histone H1 is known to be an integral part of chromatin within the nucleus, with a primary role of binding DNA that enters and exits from the nucleosome, and facilitating the shift in equilibrium of chromatin towards a more condensed form. However, phosphorylated histone H1 is predominantly present in the cytoplasm and as yet the functional significance of this translocation is unknown. This study also found that histone H1 is localised within the cytoplasm of neurons and astrocytes from areas affected by disease as well as amyloid plaques, supporting the hypothesis that histone H1 favoured binding to an ordered fibrillar motif. We conclude that the binding of histone H1 to a general amyloid-like motif indicates that histone H1 may play an important common role in diseases associated with amyloid-like fibrils.

Alzheimer Disease↗

PubMed2005

Dominant-negative effect of mutant valosin-containing protein in aggresome formation.

Lewy bodies (LBs) are the pathologic hallmark of Parkinson's disease. Recent studies revealed that LBs exhibit several morphologic and molecular similarities to aggresomes. Aggresomes are perinuclear aggregates representing intracellular deposits of misfolded proteins. Recently, valosin-containing protein (VCP) was one of the components of LBs, suggesting its involvement in LB formation. Here, we showed the localization of VCP in aggresomes induced by a proteasome inhibitor in cultured cells. Cells overexpressing mutant VCP (K524M: D2) showed reduced aggresome formation relative to those overexpressing wild-type and mutant (K251M: D1) VCPs. Our findings suggest that the D2 domain is involved in aggresome formation.

Adenosine Triphosphatases↗

PubMed2002

Cross linking of polyglutamine domains catalyzed by tissue transglutaminase is greatly favored with pathological-length repeats: does transglutaminase activity play a role in (CAG)(n)/Q(n)-expansion diseases?

Protein aggregates are a hallmark of Huntington's disease (HD) and other inherited neurodegenerative diseases caused by an elongated (CAG)(n) repeat in the genome and to a corresponding increase in the size of the Q(n) domain in the expressed protein. When the protein associated with HD (huntingtin) contains <35 Q repeats disease does not occur. However, an n>/=40 leads to disease. Some investigators have proposed that aggregates in the nuclei of affected cells are toxic, but other workers have suggested that the aggregates may be neutral or even protective. Whether or not they are toxic, an understanding of the processes whereby the aggregates develop may shed light on the neuropathological processes involved in the (CAG)(n)/Q(n)-expansion disorders. Q(n) domains have a tendency to non-covalently self align as 'polar zippers' rendering them less soluble, but evidence that such polar zippers occur in the aggregates in intact HD brain has so far been limited. The human brain contains at least three Ca(2+)-dependent enzymes (transglutaminases, TGases) that catalyze protein cross-linking reactions, namely TGase 1, TGase 2 (tissue transglutaminase, tTGase) and TGase 3. Q(n) aggregates have been found by several groups to be excellent substrates of tTGase. Moreover, the activity toward the Q(n) domains increases greatly as n is increased to 40 or beyond. tTGase mRNA and total TGase activity are elevated in HD brain. Moreover, some evidence suggests that Ca(2+) homeostasis is disrupted in HD brain. We propose that the combination of increased huntingtin (or huntingtin fragment containing the Q(n) domain) in the nucleus, increased the ability of the Q(n) domains to act as substrate, increased Ca(2+) levels and increased inherent TGase activity all contribute to increased cross-linking of proteins in HD brain. At first the proteasome machinery can recognize and degrade the cross-linked proteins, but over time the proteasome machinery may be overwhelmed and protein aggregates will accumulate.

Humans↗

PubMed2005

Axonal transport defects: a common theme in neurodegenerative diseases.

A core pathology central to most neurodegenerative diseases is the misfolding, fibrillization and aggregation of disease proteins to form the hallmark lesions of specific disorders. The mechanisms underlying these brain-specific neurodegenerative amyloidoses are the focus of intense investigation and defective axonal transport has been hypothesized to play a mechanistic role in several neurodegenerative disorders; however, this hypothesis has not been extensively examined. Discoveries of mutations in human genes encoding motor proteins responsible for axonal transport do provide direct evidence for the involvement of axonal transport in neurodegenerative diseases, and this evidence is supported by studies of animal models of neurodegeneration. In this review, we summarize recent findings related to axonal transport and neurodegeneration. Focusing on specific neurodegenerative diseases from a neuropathologic perspective, we highlight discoveries of human motor protein mutations in some of these diseases, as well as illustrate new insights from animal models of neurodegenerative disorders. We also review the current understanding of the biology of axonal transport including major recent findings related to slow axonal transport.

Animals↗

PubMed2005

Sequential generation of two structurally distinct ovine prion protein soluble oligomers displaying different biochemical reactivities.

In pathologies due to protein misassembly, low oligomeric states of the misfolded proteins rather than large aggregates play an important biological role. In prion diseases the lethal evolution is associated with formation of PrP(Sc), a misfolded and amyloid form of the normal cellular prion protein PrP. Although several molecular mechanisms were proposed to account for the propagation of the infectious agent, the events responsible for cell death are still unclear. The correlation between PrP(C) expression level and the rate of disease evolution on one side, and the fact that PrP(Sc) deposition in brain did not strictly correlate with the apparition of clinical symptoms on the other side, suggested a potential role for diffusible oligomers in neuronal death. To get better insight into the molecular mechanisms of PrP(C) oligomerization, we studied the heat-induced oligomerization pathway of the full-length recombinant ovine PrP at acidic pH. This led to the irreversible formation of two well-identified soluble oligomers that could be recovered by size-exclusion chromatography. Both oligomers displayed higher beta-sheet content when compared to the monomer. A sequential two-step multimolecular process accounted for the rate of their formation and their ratio partition, both depending on the initial protein concentration. Small-angle X-ray scattering allowed the determination of the molecular masses for each oligomer, 12mer and 36mer, as well as their distinct oblate shapes. The two species differed in accessibility of polypeptide chain epitopes and of pepsin-sensitive bonds, in a way suggesting distinct conformations for their monomeric unit. The conversion pathway leading to these novel oligomers, displaying contrasted biochemical reactivities, might be a clue to unravel their biological roles.

Animals↗

PubMed2006

Fluoro-Jade: new fluorescent marker of Rosenthal fibers.

Rosenthal fibers are homogeneous eosinophilic masses found in astrocytes that are composed of glial fibrillary acidic protein (GFAP) aggregates along with chaperone proteins and other unknown components. Rosenthal fiber formation is a pathological hallmark of Alexander disease and its detection is diagnostically significant. However, the lack of a specific fluorescent marker has greatly limited the histochemical characterization of Rosenthal fibers. Here, we report for the first time a fluorescent marker of Rosenthal fibers called Fluoro Jade. Fluoro Jade-positive masses were seen in samples of Alexander disease brain, pilocytic astrocytoma, and in brain tissue from a mouse model of Alexander disease. Fluoro Jade co-labeled tissue samples stained with GFAP immunofluorescence. Our results indicated that Fluoro Jade labeled Rosenthal fibers, and that Rosenthal fibers could be labeled with antibodies of interest in combination with Fluoro Jade staining.

Alexander Disease↗

PubMed2026

Progress towards a biotypic biomarker profile for amyotrophic lateral sclerosis-frontotemporal spectrum disorders.

Determining the optimal timing of disease-modifying therapies for neurodegenerative disorders will necessitate identification of when the underlying pathobiological process becomes active, well in advance of the point at which clinical manifestions appear. Phenoconversion, the emergence of clinically manifest syndomes, may be preceded by years to decades of silent pathobiological activity that can only be mapped by an array of biomarkers. ALS and FTD, traditionally identified as distinct clinical syndromes, are increasingly recognized to exist along a spectrum of clinical syndromes with shared genetic risk and shared underlying pathology. This clinicopathological spectrum is underpinned by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) as the common neuropathological hallmark. In contrast, the majority of neuropathologically-defined frontotemporal lobar degeneration (FTLD) is associated with alterations in either TDP-43 metabolism (FTLD-TDP) or of the microtubule associated protein tau (FTLD-tau), with a smaller percentage associated with either autosomal dominant genetic mutations or impairments in the ubiquitin proteasome system. As the field of neurodegenerative disorders increasingly shifts towards the frameworks of a pathobiological definition of disease, there is a growing imperative to develop biomarkers that reflect the varied pathobiologies that underly these disorders, and to determine the sensitivity of such biomarkers to detect the presence of these pathobiologies before phenoconversion. To that end, an international workshop was convened in London, Canada in 2025 to review the evidence for existing or evolving biomarkers suitable for (1) the detection of either ALS or FTD pathobiology prior to phenoconversion and/or (2) predict phenoconversion in at risk individuals. Such biomarkers might be conceptualized as "biotypic biomarkers", capturing their ability to describe an underlying pathophysiology whilst being agnostic to the emergent clinical manifestations. Whereas no single biotypic marker is yet able to predict the emergence of ALS, FTD or their intersection, a multimodal approach to developing a biotypic biomarker profile holds promise for the detection of relevant pathobiological processes. The strength of such an approach would be augmented by also addressing issues of resiliency/susceptibility both in terms of genetic risk susceptibility profiles and developing sensitive biomarkers of genomic and cellular aging. By including such nontraditional markers of disease, a more robust picture of not only the degenerative process but also of those factors that might potentially mitigate or drive a heightened probability of disease can be derived.

cryptic exons↗

PubMed2006

Cellular tau pathology and immunohistochemical study of tau isoforms in sporadic tauopathies.

Pathological inclusions in neurons and glial cells containing fibrillary aggregates of abnormally hyperphosphorylated tau protein are characteristic features in sporadic tauopathies. In the first part of this paper we outline the morphological features of some major sporadic tauopathies. In the second part, to better define the tau isoform composition, we report on the immunohistochemistry of tau isoforms in autopsied brains, including two cases with AD, two with diffuse neurofibrillary tangles with calcification, four with Pick's disease with Pick bodies (PiD), seven with progressive supranuclear palsy (PSP), six with corticobasal degeneration (CBD) and seven cases with argyrophilic grain disease. We used two monoclonal antibodies, RD3 and RD4, and a polyclonal antibody for exon 10 that effectively distinguish between three-repeat (3R) tau and four-repeat (4R) tau. Neuronal neurofibrillary tangles (NFT) in AD and diffuse neurofibrillary tangles with calcification contained both 3R-tau and 4R-tau. The Pick bodies were immunopositive for 3R-tau in two cases; however, in two other cases they were mainly immunopositive for 4R-tau. Thus, Pick bodies demonstrated heterogeneity. 3R-tau PiD contained 3R-tau glial inclusions, and 4R-tau PiD contained mainly 4R-tau glial inclusions. Glial inclusions were more abundant in 4R-tau PiD cases. In progressive supranuclear palsy and CBD, both neuronal and glial tau accumulation forming NFF, pretangles, tuft-shaped astrocytes, astrocytic plaques, coiled bodies and threads demonstrated 4R-tau in the cerebral cortices, although in the basal ganglia and brainstem neuronal and glial inclusions were occasionally immunopositive for 3R-tau in addition to 4R-tau. Argyrophilic grains (AG) were immunopositive for 4R-tau, although pretangles were weakly stained for 4R-tau. Thus the immunoreactivity for 4R-tau was different between AG and pretangles. Therefore, the isoform composition on immunohistochemical study showed heterogeneity in PiD, and was not uniform in the basal ganglia and brain stem in PSP and CBD. It is suggested that the isoform composition of sporadic tauopathies may have a spectrum in individual cases, and cellular isoform composition may differ in various brain regions.

Aged↗