SEARCH · PubMed Health

Results for “Protein Aggregation, Pathological”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMedDate not supplied

Cell death mechanisms in neurodegeneration.

Progressive cell loss in specific neuronal populations often associated with typical cytoskeletal protein aggregations is a pathological hallmark of neurodegenerative disorders, but the nature, time course and molecular causes of cell death and their relation to cytoskeletal pathologies are still unresolved. Apoptosis or alternative pathways of cell death have been discussed in Alzheimer's disease and other neurodegenerative disorders. Apoptotic DNA fragmentation in human brain as a sign of neuronal injury is found too frequent as to account for continuous neuron loss in these slowly progressive processes. Morphological studies revealed extremely rare apoptotic neuronal death in Alzheimer's disease but yielded mixed results for Parkinson's disease and other neurodegenerative disorders. Based on recent data in human brain, as well as in animal and cell culture models, a picture is beginning to emerge suggesting that, in addition to apoptosis, other forms of programmed cell death may participate in neurodegeneration. Better understanding of the molecular players will further elucidate the mechanisms of cell death in these disorders and their relations to cytoskeletal abnormalities. Susceptible cell populations in a proapoptotic environment show increased vulnerability towards multiple noxious factors discussed in the pathogenesis of neurodegeneration. In conclusion, although many in vivo and in vitro data are in favor of apoptosis involvement in neurodegenerative processes, there is considerable evidence that very complex events may contribute to neuronal death with possible repair mechanisms, the elucidation of which may prove useful for future prevention and therapy of neurodegenerative disorders.

Alzheimer Disease↗

PubMed2002

Presenile dementia syndromes: an update on taxonomy and diagnosis.

The four major degenerative dementias that often begin in presenescence: are reviewed. These are Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, and Creutzfeldt-Jakob disease. Their epidemiological, genetic, and clinical features are reviewed, and controversies in taxonomy arising from recent discoveries described. Particular attention is given to the pathological role of protein aggregation, which appears to be a factor in each disease.

Aged↗

PubMed2005

Tau protein as a differential biomarker of tauopathies.

Microtubule-associated Tau proteins are the basic component of intraneuronal and glial inclusions observed in many neurological disorders, the so-called tauopathies. Many etiological factors, phosphorylation, splicing, and mutations, relate Tau proteins to neurodegeneration. Molecular analysis has revealed that hyperphosphorylation and abnormal phosphorylation might be one of the important events in the process leading to tau intracellular aggregation. Specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution, could characterize five main classes of tauopathies. A direct correlation has been established between the regional brain distribution of tau pathology and clinical symptoms; for instance progressive involvement of neocortical areas is well correlated to the severity of dementia in Alzheimer's disease, overall suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. Recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies. Overall, a better knowledge of the etiological factors responsible for the aggregation of tau proteins in brain diseases is essential for development of future differential diagnosis and therapeutic strategies. They would hopefully find their application against Alzheimer's disease but also in all neurological disorders for which a dysfunction of Tau biology has been identified.

Alternative Splicing↗

PubMedDate not supplied

Coexpression and accumulation of ubiquitin +1 and ZZ proteins in livers of children with alpha(1)-antitrypsin deficiency.

The ZZ variant of alpha(1)-antitrypsin deficiency (AATD) is well known to cause liver damage and cirrhosis in some affected children. Ubiquitin abnormality was recently shown to be significant in AATD in childhood cirrhosis. Molecular misreading (MM), defined as faulty transcription of genomic information from DNA into mRNA, as well as its translation into mutant proteins, has been documented in many pathologic processes where aggregation of abnormal proteins occurs. The misread protein, ubiquitin-B(+1) (UBB(+1)), was recently identified in the hallmarks of various neurological disorders. The objective of this study was to determine whether MM of ubiquitin occurs in AATD. Twelve explanted liver specimens from AATD-affected children with cirrhosis were retrieved from archival sources, along with 10 control liver specimens obtained from autopsies of age-matched children with no clinical, gross anatomic, or histologic evidence of liver disease. Double immunofluorescence studies using rabbit polyclonal antibodies against UBB(+1) and AAT were performed on consecutively sectioned tissue. UBB(+1) immunoreactivity was colocalized with AAT in all cirrhotic AATD livers. The control livers were consistently negative. Ubiquitin MM is prominent in AATD-affected cirrhotic livers. This indicates that for children with AATD and cirrhosis, ubiquitin MM is a necessary cofactor to the aggregation of mutant ZZ isoform of AATD.

Adolescent↗

PubMed1999

Polyglutamine domain proteins with expanded repeats bind neurofilament, altering the neurofilament network.

Proteins with expanded polyglutamine (polyQ) repeats cause eight inherited neurodegenerative diseases. Nuclear and cytoplasmic polyQ protein is a common feature of these diseases, but its role in cell death remains debatable. Since the neuronal intermediate filament network is composed of neurofilament (NF) and NF abnormalities occur in neurodegenerative diseases, we examined whether pathologic-length polyQ domain proteins interact with NF. We expressed polyQ-green fluorescent fusion proteins (GFP) in a neuroblast cell line, TR1. Pathologic-length polyQ-GFP fusion proteins form large cytoplasmic aggregates surrounded by neurofilament. Immunoisolation of pathologic-length polyQ proteins co-isolated 68 kD NF protein demonstrating molecular interaction. These observations suggest that polyQ interaction with NF is important in the pathogenesis of the polyglutamine repeat diseases.

Amino Acid Sequence↗

PubMed2004

Accelerated extinction of conditioned taste aversion in P301L tau transgenic mice.

Neurofibrillary tangles, insoluble protein deposits composed of filamentous tau aggregates, are neuropathological hallmarks of Alzheimer's disease and familial frontotemporal dementia (FTDP-17). Transgenic mice expressing the FTDP-17 mutation P301L of tau recapitulate key features of the human pathology, that is, tau proteins aggregate and neurofibrillary tangles begin to appear in the amygdala at 6 months of age. To detect early signs of tau aggregate-associated changes, we investigated behavioral alterations and cognitive deficits in such mice using an amygdala-specific test battery for anxiety-related and cognitive behavior. P301L mice had anxiety levels not different from wild-types, but their exploratory behavior was significantly increased. Acquisition of a fear response to tone and context as well as taste aversion was comparable to wild-types. However, extinction of a conditioned taste aversion was significantly accelerated. We conclude that already aggregation of tau proteins not yet accompanied by massive formation of neurofibrillary tangles causes selective behavioral deficits.

Animals↗

PubMed2002

Calpain activation in neurodegenerative diseases: confocal immunofluorescence study with antibodies specifically recognizing the active form of calpain 2.

The calcium-activated protease calpain cleaves a variety of biologically important proteins and serves, therefore, as a key regulator of many cellular functions. Activation of both main isoforms, calpain 1 and calpain 2, was demonstrated previously in Alzheimer's disease. In this report, antibodies specifically recognizing the active form of calpain 2 were used to investigate calpain 2 activation in a broad range of neurodegenerative diseases, utilizing multiple-label confocal immunofluorescence imaging. With rare exceptions, the active form of calpain 2 was found in colocalization with hyperphosphorylated tau protein. Aggregates of mutated huntingtin, alpha-synuclein, or unidentified protein in motor neuron disease type of frontotemporal dementia were always negative. These findings indicate that calpain 2 activation is not a general response to protein aggregation. In tauopathies, more pathological inclusions were labeled for hyperphosphorylated tau than for activated calpain 2. The extent of colocalization varied in both a disease-specific and cell-type specific manner. The active form of calpain 2 was detected in 50-75% of tau neurofibrillary pathology in Alzheimer's disease, Alzheimer neurofibrillary changes and Down's syndrome, as well as in the accompanying Alzheimer-type tau pathology in diffuse Lewy bodies disease, progressive supranuclear palsy, and corticobasal degeneration. For glial cells, only 10-25% of tuft-shaped astrocytes, glial plaques, or coiled bodies contained activated calpain 2. The majority of Pick bodies were negative. The association of calpain 2 activation with hyperphosphorylated tau might be the result of an attempt by the calpain proteolytic system to degrade the tau protein aggregates. Alternatively, calpain 2 could be directly involved in tau hyperphosphorylation by modulating protein kinase activities. Overall, these results provide evidence of the important role of the calpain proteolytic system in the pathogenesis of neurodegenerative diseases with tau neurofibrillary pathology.

Adolescent↗

PubMed2006

Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid beta, amyloid beta40, and amyloid beta42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice.

Accumulation of amyloid beta protein (Abeta) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting Abeta are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-Abeta single-chain variable fragments (scFvs) as a potentially safer form of anti-Abeta immunotherapy. We have generated and characterized three anti-Abeta scFvs that recognize Abeta 1-16, Abeta x-40, or Abeta x-42. To achieve widespread brain delivery, constructs expressing these anti-Abeta scFvs were packaged into adeno-associated virus (AAV) vectors and injected into the ventricles of postnatal day 0 (P0) amyloid precursor protein CRND8-transgenic mice. Intracranial delivery of AAV to neonatal mice resulted in widespread neuronal delivery. In situ expression of each of the anti-Abeta scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased Abeta deposition by 25-50%. These data suggest that intracranial anti-Abeta scFv expression is an effective strategy to attenuate amyloid deposition. As opposed to transgenic approaches, these studies also establish a "somatic brain transgenic" paradigm to rapidly and cost-effectively evaluate potential modifiers of AD-like pathology in AD mouse models.

Alzheimer Disease↗

PubMed2004

Pseudophosphorylation of tau protein alters its ability for self-aggregation.

Filamentous tau protein deposits are a pathological hallmark of a group of neurodegenerative disorders (tauopathies). Tau protein in these aggregates is highly phosphorylated at different phosphorylation sites. Although tau filaments can be formed by heparin-induced aggregation of unphosphorylated recombinant tau, it is not known how tau phosphorylation modulates aggregation behaviour. Analysis of the effect of tau phosphorylation at defined single or multiple sites is hampered by the low specificity of protein kinases and the highly dynamic turnover of phosphorylation in vivo. To overcome this problem we employed site-directed mutagenesis to convert serine and threonine to aspartic acid or glutamic acid, which introduce a negative charge and conformational change that mimic phosphorylation. We tested 14 different mutated tau proteins for their propensity for self-aggregation and formation of tau filaments. Tau aggregation was monitored with thioflavin S fluorescence in the presence of different inducers such as heparin, Al3+, Fe2+ and Fe3+. We found that mutations in the N-terminal portion up to amino acid 208 mainly suppress tau aggregation, whereas mutations in the C-terminal region mainly lead to an enhanced aggregation. Mutations in the middle portion of tau showed a mixed picture of suppression and enhancement of aggregation. A single amino acid change Ser422Glu has aggregation-favouring properties with all four inducers.

Amino Acid Substitution↗

PubMed2005

Expression and purification of a recombinant peptide from the Alzheimer's beta-amyloid protein for solid-state NMR.

Fibrillar protein aggregates contribute to the pathology of a number of disease states. To facilitate structural studies of these amyloid fibrils by solid-state NMR, efficient methods for the production of milligram quantities of isotopically labeled peptide are necessary. Bacterial expression of recombinant amyloid proteins and peptides allows uniform isotopic labeling, as well as other patterns of isotope incorporation. However, large-scale production of recombinant amyloidogenic peptides has proven particularly difficult, due to their inherent propensity for aggregation and the associated toxicity of fibrillar material. Yields of recombinant protein are further reduced by the small molecular weights of short amyloidogenic fragments. Here, we report high-yield expression and purification of a peptide comprising residues 11-26 of the Alzheimer's beta-amyloid protein (Abeta(11-26)), with homoserine lactone replacing serine at residue 26. Expression in inclusion bodies as a ketosteroid isomerase fusion protein and subsequent purification under denaturing conditions allows production of milligram quantities of uniformly labeled (13)C- and (15)N-labeled peptide, which forms amyloid fibrils suitable for solid-state NMR spectroscopy. Initial structural data obtained by atomic force microscopy, electron microscopy, and solid-state NMR measurements of Abeta(11-26) fibrils are also presented.

Amino Acid Sequence↗

PubMed2003

A neurotoxic peripherin splice variant in a mouse model of ALS.

Peripherin, a neuronal intermediate filament (nIF) protein found associated with pathological aggregates in motor neurons of patients with amyotrophic lateral sclerosis (ALS) and of transgenic mice overexpressing mutant superoxide dismutase-1 (SOD1G37R), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. Mouse peripherin is unique compared with other nIF proteins in that three peripherin isoforms are generated by alternative splicing. Here, the properties of the peripherin splice variants Per 58, Per 56, and Per 61 have been investigated in transfected cell lines, in primary motor neurons, and in transgenic mice overexpressing peripherin or overexpressing SOD1G37R. Of the three isoforms, Per 61 proved to be distinctly neurotoxic, being assembly incompetent and inducing degeneration of motor neurons in culture. Using isoform-specific antibodies, Per 61 expression was detected in motor neurons of SOD1G37R transgenic mice but not of control or peripherin transgenic mice. The Per 61 antibody also selectively labeled motor neurons and axonal spheroids in two cases of familial ALS and immunoprecipitated a higher molecular mass peripherin species from disease tissue. This evidence suggests that expression of neurotoxic splice variants of peripherin may contribute to the neurodegenerative mechanism in ALS.

Alternative Splicing↗

PubMed2004

Short amino acid stretches can mediate amyloid formation in globular proteins: the Src homology 3 (SH3) case.

Protein misfolding and deposition underlie an increasing number of debilitating human disorders. We have shown that model proteins unrelated to disease, such as the Src homology 3 (SH3) domain of the p58alpha subunit of bovine phosphatidyl-inositol-3'-kinase (PI3-SH3), can be converted in vitro into assemblies with structural and cytotoxic properties similar to those of pathological aggregates. By contrast, homologous proteins, such as alpha-spectrin-SH3, lack the capability of forming amyloid fibrils at a measurable rate under any of the conditions we have so far examined. However, transplanting a small sequence stretch (6 aa) from PI3-SH3 to alpha-spectrin-SH3, comprising residues of the diverging turn and adjacent RT loop, creates an amyloidogenic protein closely similar in its behavior to the original PI3-SH3. Analysis of specific PI3-SH3 mutants further confirms the involvement of this region in conferring amyloidogenic properties to this domain. Moreover, the inclusion in this stretch of two consensus residues favored in SH3 sequences substantially inhibits aggregation. These findings show that short specific amino acid stretches can act as mediators or facilitators in the incorporation of globular proteins into amyloid structures, and they support the suggestion that natural protein sequences have evolved in part to code for structural characteristics other than those included in the native fold, such as avoidance of aggregation.

Amino Acid Sequence↗

PubMed1999

Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig.

Brain trauma in humans increases the risk for developing Alzheimer disease (AD) and may induce the acute formation of AD-like plaques containing amyloid beta (A beta). To further explore the potential link between brain trauma and neurodegeneration, we conducted neuropathological studies using a pig model of diffuse brain injury. Brain injury was induced in anesthetized animals via nonimpact head rotational acceleration of 110 degrees over 20 ms in the coronal plane (n = 15 injured, n = 3 noninjured). At 1, 3, 7, and 10 days post-trauma, control and injured animals were euthanized and immunohistochemical analysis was performed on brain sections using antibodies specific for A beta, beta-amyloid precursor protein (betaPP), tau, and neurofilament (NF) proteins. In addition to diffuse axonal pathology, we detected accumulation of A beta and tau that colocalized with immunoreactive betaPP and NF in damaged axons throughout the white matter in all injured animals at 3-10 days post-trauma. In a subset of brain injured animals, diffuse A beta-containing plaque-like profiles were found in both the gray and white matter, and accumulations of tau and NF rich inclusions were observed in neuronal perikarya. These results show that this pig model of diffuse brain injury is characterized by accumulations of proteins that also form pathological aggregates in AD and related neurodegenerative diseases.

Amyloid beta-Peptides↗

PubMed2003

Recent developments in the neuropathological diagnosis of Parkinson's disease and parkinsonism.

The diagnosis of Parkinson's disease (PD) is based mainly on clinical criteria. Large clinicopathological studies reveal however a different diagnosis in up to 25% of the cases (Hughes et al., 1992). Recent advances in molecular biology have shown that some proteins, especially tau and alpha-synuclein, play an essential role in the pathogenesis of parkinsonian and dementing disorders. Such diseases are now classified as tauopathies and synucleinopathies. Progressive supranuclear palsy and corticobasal degeneration are the major tauopathies. To the synucleinopathies belong PD, Lewy body dementia and multiple system atrophy. In pathological conditions abnormal proteins will aggregate in neurons and glial cells and form inclusion bodies. Lewy bodies are the hallmark of Parkinson's disease and Lewy body dementia. Identification of these inclusions and other specific lesions in parkinsonian disorders is facilitated by the routine application on formalin fixed brain of immunohistochemistry for alpha-synuclein, tau and ubiquitin. The purpose of this paper is to briefly review and illustrate the value of these new techniques in the postmortem diagnosis of parkinsonian disorders. Neuropathological examination of the brain is however time consuming and immunohistochemistry represents additional costs. As the selection of brain samples for microscopical examination and antibodies for immunohistochemistry depends on the underlying pathology, some clinical information should be provided to the pathologist such as the clinical diagnosis and when indicated the results of brain imaging studies. A close co-operation between the neurologist and neuropathologist is thus essential to select the most appropriate brains for complete neuropathological investigation.

Brain↗

PubMed2005

Small N-terminal mutant huntingtin fragments, but not wild type, are mainly present in monomeric form: Implications for pathogenesis.

N-terminal fragments of huntingtin containing an expanded polyglutamine stretch play an important role in the molecular pathogenesis of Huntington's disease. Their ultimate accumulation in insoluble protein aggregates constitutes an important pathological hallmark of Huntington's disease. We report on systematic biochemical comparison studies of soluble wild type and mutant N-terminal huntingtin fragments. The results show that soluble wild type exon 1 fragments are predominantly present in higher molecular weight complexes with a molecular size of approximately 300 kDa, while their mutant counterparts are mainly present in their monomeric form. In contrast, longer N-terminal fragments corresponding to peptides produced by caspase cleavage do not display these differential properties. These findings suggest that especially an increased amount of monomeric form of small N-terminal mutant huntingtin fragments may facilitate aberrant interactions both with itself via the polyglutamine stretch and with other proteins and thereby contribute to molecular pathogenesis.

Animals↗

PubMed2000

Aggregates of mutant protein appear progressively in dendrites, in periaxonal processes of oligodendrocytes, and in neuronal and astrocytic perikarya of mice expressing the SOD1(G93A) mutation of familial amyotrophic lateral sclerosis.

Mice expressing the G93A and other mutations of Cu,Zn superoxide dismutase (SOD1(G93A)) are valid models for the familial form of amyotrophic lateral sclerosis (FALS) with SOD1 mutations and, probably, for sporadic ALS. Adult mice become progressively paralyzed and show most of the histopathological lesions reported in sporadic ALS, i.e. neuronal loss, astrogliosis, ubiquitin and Lewy body-like inclusions, dystrophic axons and fragmentation of the Golgi apparatus (GA) of motor neurons. In transgenic mice, the mutant protein and ubiquitin aggregate within pathological 13 nm thick filaments [Stieber A, Gonatas JO, Gonatas NK. J Neurol Sci 2000;173:53-62]. This immunocytochemical and quantitative study of mice expressing SOD1(G93A) establishes the chronological order and cellular localization of aggregates of SOD1 and their correlation with fragmentation of the GA. Young asymptomatic mice expressing SOD1(G93A) showed aggregates of mutant SOD1 within neurites, prior to the detection of SOD1 in the perikarya of spinal cord motor neurons and astrocytes. Both dendrites and the periaxonal oligodendroglial cytoplasm, surrounding atrophic axons, contained SOD1 as revealed by immunoelectron microscopy The perikarya of a small percentage of spinal cord motor neurons contained both fragmented GA and aggregates of SOD1; however, about 50% of motor neurons with fragmented GA did not contain SOD1 in the perikaryon, suggesting that aggregates of mutant protein may not directly cause fragmentation of the GA. The mechanism of the putative toxic effect by the mutant protein remains to be clarified. The isolation and biochemical characterization of the filamentous aggregates of mutant protein and ubiquitin from spinal cords of transgenic mice expressing mutations of the SOD1 gene may offer clues on pathogenetic mechanisms.

Amyotrophic Lateral Sclerosis↗

PubMed2005

SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy.

Conjugation of the small ubiquitin-like modifier, SUMO-1, to target proteins is linked to the regulation of multiple cellular pathways, including nucleocytoplasmic trafficking, cell cycle progression, the ubiquitin-proteasome system and apoptosis. Recently, the accumulation of SUMOylated proteins in pathological neuronal intranuclear aggregates has been found in several neurodegenerative diseases. The aim of our study was to examine SUMO-1 in the alpha-synucleinopathy diseases, Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). We conducted anti-SUMO-1 immunostaining of fixed brain tissue sections and smears of unfixed brain tissue homogenates of DLB and MSA cases. We found that oligodendroglial cytoplasmic inclusions, the alpha-synuclein-positive cytoplasmic aggregates that characterize MSA, exhibit robust punctate SUMO-1 immunostaining, marking discrete submicron-sized subdomains within the inclusion bodies. Lewy bodies in smears of DLB tissue homogenates showed similar SUMO-1-positive structures, although these were not detected in fixed tissue. In cell culture experiments, we found that the nuclear and perinuclear accumulation of SUMO-1 aggregates could be induced in glioma cells by chemical inhibition of proteasomal protein degradation.

Biomarkers↗

PubMed2006

Preparation of soluble infectious samples from scrapie-infected brain: a new tool to study the clearance of transmissible spongiform encephalopathy agents during plasma fractionation.

BACKGROUND: Concern about the safety of blood, blood components, and plasma-derived products with respect to prions has increased since the report of two blood-related infections of variant Creutzfeldt-Jakob disease in the United Kingdom. Efforts were directed toward the development of procedures able to remove or inactivate prions from blood components or plasma-derived products with brain fractions of transmissible spongiform encephalopathy (TSE)-infected rodents as spiking materials. These spiking materials, however, are loaded with pathological prion protein (PrP(TSE)) aggregates that are likely not associated to blood infectivity. The presence of these aggregates may invalidate these studies. STUDY DESIGN AND METHODS: Brains from 263K scrapie-infected hamsters were suspended in 10 percent phosphate-buffered saline. After low-speed centrifugation, the supernatant was collected and ultracentrifuged at 220,000 x g at 25 degrees C for 30 minutes. The high-speed supernatants (S(HS)) and pellets were collected; the proteinase-resistant PrP(TSE) was measured by Western blot and infectivity by intracerebral inoculation into weanling hamsters. RESULTS: A substantial amount of prion infectivity (more than 10(5) LD(50) per mL of a 10% suspension of brain tissues) is present in the S(HS) fraction of 263K scrapie-infected hamster brains. Concomitantly, this fraction contains none or only traces of PrP(TSE) in its aggregate form. CONCLUSION: This study describes a simple and fast protocol to prepare infectious material from 263K scrapie-infected brains that is not contaminated with PrP(TSE) aggregates. This S(HS) fraction is likely to be the most relevant material for endogenous spiking of human blood in validation experiments aimed at demonstrating procedures to remove or inactivate TSE infectious agents.

Animals↗