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Results for “Protein Aggregation, Pathological”

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PubMed2005

Molecular pathogenesis of Parkinson's disease.

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

Animals↗

PubMed1989

[Rheologic findings in patients with Eales disease].

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

Adolescent↗

PubMed2005

Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies.

Parkinson disease (PD) and dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal alpha-synuclein and ubiquitin in protein aggregates conforming Lewy bodies and Lewy neurites. Ubiquitin C-terminal hydrolase-1 (UCHL-1) disassembles polyubiquitin chains to increase the availability of free monomeric ubiquitin to the ubiquitin proteasome system (UPS) thus favoring protein degradation. Since mutations in the UCHL-1 gene, reducing UPS activity by 50%, have been reported in autosomal dominant PD, and UCHL-1 inhibition results in the formation of alpha-synuclein aggregates in mesencephalic cultured neurons, the present study was initiated to test UCHL-1 mRNA and protein levels in post-mortem frontal cortex (area 8) of PD and DLB cases, compared with age-matched controls. TaqMan PCR assays, and Western blots demonstrated down-regulation of UCHL-1 mRNA and UCHL-1 protein in the cerebral cortex in DLB (either in pure forms, not associated with Alzheimer disease: AD, and in common forms, with accompanying AD changes), but not in PD, when compared with age-matched controls. Interestingly, UCHL-1 mRNA and protein expressions were reduced in the medulla oblongata in the same PD cases. Moreover, UCHL-1 protein was decreased in the substantia nigra in cases with Lewy body pathology. UCHL-1 down-regulation was not associated with reduced protein levels of several proteasomal subunits, including 20SX, 20SY, 19S and 11Salpha. Yet UCHL-3 expression was reduced in the cerebral cortex of PD and DLB patients. Together, these observations show reduced UCHL-1 expression as a contributory factor in the abnormal protein aggregation in DLB, and points UCHL-1 as a putative therapeutic target in the treatment of DLB.

Aged↗

PubMed2006

Ubiquitin-conjugating enzyme E2-25K increases aggregate formation and cell death in polyglutamine diseases.

Polyglutamine diseases are characterized by neuronal intranuclear inclusions of expanded polyglutamine proteins, which are also ubiquitinated, indicating impairment of the ubiquitin-proteasome system. E2-25K (Hip2), an ubiquitin-conjugating enzyme, interacts directly with huntingtin and may mediate ubiquitination of the neuronal intranuclear inclusions in Huntington disease. E2-25K could thus modulate aggregation and toxicity of expanded huntingtin. Here we show that E2-25K is involved in aggregate formation of expanded polyglutamine proteins and polyglutamine-induced cell death. Both a truncated mutant, lacking the catalytic tail domain, as well as a full antisense sequence, reduce aggregate formation. Strikingly, both E2-25K mutants also reduced polyglutamine-induced cell death. In postmortem brain material of both Huntington disease and SCA3, E2-25K staining of polyglutamine aggregates was observed in a subset of neurons bearing intranuclear neuronal inclusions. These results demonstrate that targeting by ubiquitination plays an important role in the pathology of polyglutamine diseases.

Brain↗

PubMed2005

Polyglutamine is not all: the functional role of the AXH domain in the ataxin-1 protein.

A family of neurodegenerative diseases is associated with anomalous expansion of a polyglutamine tract in the coding region of the corresponding proteins. The current working hypothesis is that polyglutamine diseases are caused by misfolding and aggregation of the proteins with a process dictated by the polyglutamine tracts, although increasing evidence suggests an involvement of the protein context in modulating these properties. Here, we show that the AXH domain of ataxin-1, the protein involved in spinocerebellar ataxia type-1, is the region responsible for the transcriptional repression activity of ataxin-1 and participates in protein aggregation. In vitro, the isolated domain undergoes a conformational transition towards a beta-enriched structure associated with aggregation and amyloid fibre formation spontaneously and without need for destabilizing conditions. Using a transfected cell line, we demonstrate that, while determined by polyglutamine expansion, ataxin-1 aggregation is noticeably reduced by deletion of AXH or by replacement with the homologous sequence from the transcription factor HBP1, which has no known tendency to aggregate. These results provide the first direct evidence of an involvement of a region other than the polyglutamine tract in polyglutamine pathologies.

Amyloid↗

PubMed1997

Reactive oxygen species and Alzheimer's disease.

Although a consensus that Alzheimer's disease (AD) is a single disease has not been reached yet, the involvement of the amyloid precursor protein (APP) and betaA4 (A beta) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of betaA4 in cell cultures, and the findings that aggregation of betaA4 can be induced by metal-catalyzed oxidation and that free oxygen radicals may be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS may be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.

Aging↗

PubMed2002

Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (Abeta) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Abeta precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Abeta deposition. Several biochemical and molecular studies using transfected cells and transgenic animals point to mechanisms by which Abeta is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as "secretases" participate in APP processing. An enzymatic activity, beta-secretase, cleaves APP on the amino side of Abeta producing a large secreted derivative, sAPPbeta, and an Abeta-bearing membrane-associated C-terminal derivative, CTFbeta, which is subsequently cleaved by the second activity, gamma-secretase, to release Abeta. Alternatively, a third activity, alpha-secretase, cleaves APP within Abeta to the secreted derivative sAPPalpha and membrane-associated CTFalpha. The predominant secreted APP derivative is sAPPalpha in most cell-types. Most of the secreted Abeta is 40 residues long (Abeta40) although a small percentage is 42 residues in length (Abeta42). However, the longer Abeta42 aggregates more readily and was therefore considered to be the pathologically important form. Advances in our understanding of APP processing, trafficking, and turnover will pave the way for better drug discovery for the eventual treatment of AD. In addition, APP gene regulation and its interaction with other proteins may provide useful drug targets for AD. The emerging knowledge related to the normal function of APP will help in determining whether or not the AD associated changes in APP metabolism affect its function. The present review summarizes our current understanding of APP metabolism and function and their relationship to other proteins involved in AD.

Aged↗

PubMed2002

The degradation of amyloid beta as a therapeutic strategy in Alzheimer's disease and cerebrovascular amyloidoses.

The deposition of 4-kDa amyloid beta peptide in the brain is a prominent feature of several human diseases. Such process is heterogeneous in terms of causative factors, biochemical phenotype, localization and clinical manifestations. Amyloid beta accumulates in the neuropil or within the walls of cerebral vessels, and associates with dementia or stroke, both hereditary and sporadic. Amyloid beta is normally released by cells as soluble monomeric-dimeric species yet, under pathological conditions, it self-aggregates as soluble oligomers or insoluble fibrils that may be toxic to neurons and vascular cells. Lowering amyloid beta levels may be achieved by inhibiting its generation from the amyloid beta-precursor protein or by promoting its clearance by transport or degradation. We will summarize recent findings on brain proteases capable of degrading amyloid beta with a special focus on those enzymes for which there is genetic, transgenic or biochemical evidence suggesting that they may participate in the proteolysis of amyloid beta in vivo. We will also put in perspective their possible utilization as therapeutic agents in amyloid beta diseases.

Alzheimer Disease↗

PubMed2006

Expression of expanded polyglutamine proteins suppresses the activation of transcription factor NFkappaB.

A major pathological hallmark of the polyglutamine diseases is the formation of neuronal intranuclear inclusions of the disease proteins that are ubiquitinated and often associated with various transcription factors, chaperones, and proteasome components. However, how the expanded polyglutamine proteins or their aggregates elicit complex pathogenic responses in the neuronal cells is not fully understood. Here, we have demonstrated that the expression of expanded polyglutamine proteins down-regulated the NFkappaB-dependent transcriptional activity. The expression of expanded polyglutamine proteins increased the stability and the levels of IkappaB-alpha and its phosphorylated derivatives. We have also found that various NFkappaB subunits and IkappaB-alpha aberrantly interacted with the expanded polyglutamine proteins and associated with their aggregates. Finally, we have shown that several NFkappaB-dependent genes are down-regulated in the expanded polyglutamine protein-expressing cells and down-regulation of NFkappaB activity enhances expanded polyglutamine protein-induced cell death. Because the NFkappaB pathway plays a very important role in cell survival, altered regulation of this pathway in expanded polyglutamine protein-expressing cells might be linked with the disease pathogenesis.

Animals↗

PubMed1997

TNF inhibits myogenesis and downregulates the expression of myogenic regulatory factors myoD and myogenin.

The presence of TNF and other inflammatory cytokines and their receptors is detected during embryonic development, but our knowledge about the role of these proteins in differentiation and development is very limited. TNF modulates the synthesis and activity of a number of transcriptional proteins that regulate the activity of tissue specific genes, therefore it may play a role in normal development. Since its synthesis is upregulated by stress and infections, it may also participate in the induction of pathological developmental processes and malformation. We investigated the effect of TNF in an in vitro differentiation system using C2 myoblasts. This inflammatory cytokine exerted a positive effect on the early steps of the process: it enhanced the proliferation and aggregation of myoblast cells. In contrast, TNF strongly inhibited the expression of those myogenic transcription factors (myoD and myogenin), which are known to be responsible for upregulated activity of muscle specific genes (like the genes of the myofilament proteins), and blocked the synthesis of mRNAs of myogenic differentiation markers (like skeletal alpha-actin, myosin heavy and light chains). As a result, these cells did not synthesize myofilament proteins and the organization of myofilaments did not take place in TNF-treated myoblasts.

Actin Cytoskeleton↗

PubMed1997

Amyloid precursor protein, copper and Alzheimer's disease.

Although a consensus that Alzheimer's disease (AD) is a single disease has not yet been reached, the involvement of the amyloid precursor protein (APP) and beta A4 (A beta) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of beta A4 in cell cultures, and the findings that aggregation of beta A4 can be induced by metal-catalyzed oxidation and that free oxygen radicals might be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS might be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.

Alzheimer Disease↗

PubMed2000

Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA.

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. The autosomal dominant form of the disease is caused by short (GCG)(8-13) expansions in the PABP2 gene. This gene encodes the poly(A) binding protein 2 (PABP2), an abundant nuclear protein that binds with high affinity to nascent poly(A) tails, stimulating their extension and controlling their length. In this work we report that PABP2 is detected in filamentous nuclear inclusions, which are the pathological hallmark of OPMD. Using both immunoelectron microscopy and fluorescence confocal microscopy, the OPMD-specific nuclear inclusions appeared decorated by anti-PABP2 antibodies. In addition, the inclusions were labeled with antibodies directed against ubiquitin and the subunits of the proteasome and contained a form of PABP2 that was more resistant to salt extraction than the protein dispersed in the nucleoplasm. This suggests that the polyalanine expansions in PABP2 induce a misfolding and aggregation of the protein into insoluble inclusions, similarly to events in neurodegenerative diseases caused by CAG/polyglutamine expansions. No significant differences were observed in the steady-state poly(A) tail length in OPMD and normal myoblasts. However, the nuclear inclusions were shown to sequester poly(A) RNA. This raises the possibility that in OPMD the polyalanine expansions in the PABP2 protein may interfere with the cellular traffic of poly(A) RNA.

Cell Nucleus↗

PubMed2000

Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease.

Huntington's disease (HD), spinocerebellar ataxias types 1 and 3 (SCA1, SCA3), and spinobulbar muscular atrophy (SBMA) are caused by CAG/polyglutamine expansion mutations. A feature of these diseases is ubiquitinated intraneuronal inclusions derived from the mutant proteins, which colocalize with heat shock proteins (HSPs) in SCA1 and SBMA and proteasomal components in SCA1, SCA3, and SBMA. Previous studies suggested that HSPs might protect against inclusion formation, because overexpression of HDJ-2/HSDJ (a human HSP40 homologue) reduced ataxin-1 (SCA1) and androgen receptor (SBMA) aggregate formation in HeLa cells. We investigated these phenomena by transiently transfecting part of huntingtin exon 1 in COS-7, PC12, and SH-SY5Y cells. Inclusion formation was not seen with constructs expressing 23 glutamines but was repeat length and time dependent for mutant constructs with 43-74 repeats. HSP70, HSP40, the 20S proteasome and ubiquitin colocalized with inclusions. Treatment with heat shock and lactacystin, a proteasome inhibitor, increased the proportion of mutant huntingtin exon 1-expressing cells with inclusions. Thus, inclusion formation may be enhanced in polyglutamine diseases, if the pathological process results in proteasome inhibition or a heat-shock response. Overexpression of HDJ-2/HSDJ did not modify inclusion formation in PC12 and SH-SY5Y cells but increased inclusion formation in COS-7 cells. To our knowledge, this is the first report of an HSP increasing aggregation of an abnormally folded protein in mammalian cells and expands the current understanding of the roles of HDJ-2/HSDJ in protein folding.

Acetylcysteine↗

PubMed2005

[Post-mortem diagnosis of Alzheimer's disease].

Alzheimer's disease is a slowly but continuously progressive degenerative disorder of the human central nervous system seen in approximately 15% of elderly people over the age of 65 years. Morphological hallmarks of this process are intra- and extracellular protein aggregates. The intraneuronal protein aggregates are primarily made up of abnormal phosphorylated tau-protein, which builds neurofibrillary tangles, neuropil threads and dystrophic neurites in neuritic plaques. The extracellular deposits consist of amyloid beta-protein (Abeta) aggregates showing the characteristics of amyloid fibrils. The evolution of neurofibrillary changes as well as Abeta-deposition in brain regions follows a distinct hierarchical sequence spanning many decades. Abeta deposition begins in the neocortex whereas neurofibrillary pathology starts in the allocortical nerve cells of the transentorhinal region. Both transformations continue to increase in severity and expand into further areas and regions. The hierarchical pattern allows an easily understandable staging of neurofibrillary and Abeta pathology which in turn reflects the clinical gravity of the disease. According to these stages a dementing disorder can be diagnostically attributed to Alzheimer's disease.

Aged↗

PubMed2005

Inflammation of the respiratory tract is associated with CCL28 and CCR10 expression in a murine model of allergic asthma.

Mouse models and in vitro cell culture were used to examine airway expression of the mucosal chemokine CCL28. Low levels of constitutively expressed mRNA were observed in transformed murine epithelial cells, but high levels could be induced by stimulation. Cytokines that signal through NF-kappaB, including IL-1beta and TNF-alpha or via JAK-STAT pathway including oncostatin M induced CCL28 in airway epithelial cells in vitro. Immunohistochemistry of murine airway tissue revealed that constitutive expression of CCL28 protein in vivo was low and not ubiquitous. However, abundant expression was detected in epithelia and lymphoid aggregates following allergic sensitization and challenge with ovalbumin. This was accompanied by increased detection of cells expressing CCR10 protein and mRNA in inflamed airways. Taken together, these data support a role for CCL28 in contributing to allergen driven airway pathologies, show that proinflammatory cytokines can induce this signal and suggest a role for CCR10 expressing cells in airway inflammation.

Animals↗

PubMed2001

Antidenaturant drugs for cataract and other condensation diseases.

'Condensation diseases' are heterogeneous pathological conditions in which the primary pathogenetic step is the loss of solubility of specific substances, resulting in the formation of a condensed phase. Typical examples are cataract, nephrolithiasis, gallstone disease and certain rheumatic conditions in which protein denaturation, aggregation and precipitation may occur. Since the condensing molecules are often proteins, antidenaturant agents should be considered rational drugs for the treatment of these diseases. Surprisingly, however, only a few molecules with these properties are currently available for therapeutic use, including bendazac for cataract.

Cataract↗

PubMed2001

The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein.

alpha-Synuclein-containing aggregates represent a feature of a variety of neurodegenerative disorders, including Parkinson's disease (PD). However, mechanisms that promote intraneuronal alpha-synuclein assembly remain poorly understood. Because pesticides, particularly the herbicide paraquat, have been suggested to play a role as PD risk factors, the hypothesis that interactions between alpha-synuclein and these environmental agents may contribute to aggregate formation was tested in this study. Paraquat markedly accelerated the in vitro rate of alpha-synuclein fibril formation in a dose-dependent fashion. When mice were exposed to the herbicide, brain levels of alpha-synuclein were significantly increased. This up-regulation followed a consistent pattern, with higher alpha-synuclein at 2 days after each of three weekly paraquat injections and with protein levels returning to control values by day 7 post-treatment. Paraquat exposure was also accompanied by aggregate formation. Thioflavine S-positive structures accumulated within neurons of the substantia nigra pars compacta, and dual labeling and confocal imaging confirmed that these aggregates contained alpha-synuclein. The results suggest that up-regulation of alpha-synuclein as a consequence of toxicant insult and direct interactions between the protein and environmental agents are potential mechanisms leading to alpha-synuclein pathology in neurodegenerative disorders.

Animals↗

PubMed1990

[Hemorheologic changes in patients with obliterative arteriopathy of the leg before and after muscle exercise tests].

Blood and plasma viscosity, erythrocyte filtrability and blood gas analysis were determined in 25 subjects with arteriosclerosis obliterans of the lower limbs before and after a muscle exercise test. Thirty-six shear rates between 0 and 230 s1 were studied to obtain viscosity curves, and regression analysis was performed for each curve. Mean viscosity curves for pathologic and control populations were plotted. The purpose of the study was to determine whether viscosity curves for blood and plasma before and after exercise, based on a high number of measurements, can provide information on rheological changes during intermittent claudication. Practically all viscosity curves in pathologic and control subjects could be described using a hyperbolic equation. Plasma as well as blood viscosity increased in pathologic subjects after exercise. However, erythrocyte filtrability and blood gas analysis in pathologic and control subjects, and blood and plasma viscosity in control subjects, showed no statistically significant changes after exercise. It is suggested that muscle exercise in reduced blood flow conditions can alter the aggregation of macromolecular complexes of plasma proteins, which could have an influence on cell components by modifying blood rheological behavior during claudication.

Arteriosclerosis↗