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Results for “Protein Aggregation, Pathological”

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PubMed1995

Immunocytochemical characterization of Tau proteins during cerebral aging of the lemurian primate Microcebus murinus.

The immunocytochemistry of Tau proteins in the cortical pyramidal neurons of the adult microcebes has been studied, using antibodies against human normal and pathological Tau proteins. Some changes related to the age and to some pathologies were observed. In fact, during the adult life, Tau proteins appeared as very thin granulations scattered in the whole neuronal cytoplasm. With age, a part of these proteins aggregated and became like thick granules at the neuron periphery; the distribution was not uniform, and numerous neurons with aggregated Tau proteins were observed in amyloid plaque-containing brains. Abnormally phosphorylated Tau proteins were also observed in some aged animals, using an absorbed anti-PHF recognizing the pathological Tau proteins characteristic of Alzheimer's disease. This present work confirms that the microcebe is a good model for studying disfunctions involved in the normal cerebral aging and in some neurodegenerative disorders which affect humans.

Adult↗

PubMed1995

Immunocytochemical characterization of Tau proteins during cerebral aging of the lemurian primate Microcebus murinus.

Amyloid beta-Peptides↗

PubMedDate not supplied

Tau aggregation in the hippocampal formation: an ageing or a pathological process?

Tauopathy is a concept to describe different genetic or metabolic dysfunctions of tau proteins that generate most of the known dementing disorders. Tauopathy is a degenerating process that also affects the entorhinal formation, and then the hippocampal formation in ageing. In Alzheimer's disease (AD), a disease due to APP dysfunction, a similar tauopathy process in observed in neocortical areas, well correlated to cognitive impairment. One important gap of knowledge is the relationship between tauopathy in the hippocampal formation, ageing, AD, and cognitive impairment. Here we show that the multidisciplinary analysis of numerous brains from non-demented and demented patients suggests the following observations: tauopathy of the hippocampal formation in humans is age-related but not an age-dependent process, also independent of AD, but amplified by APP dysfunctions. Tauopathy in the entorhinal and hippocampal formation could be another type of pathological dysfunction of tau proteins, and a therapeutic target to delay AD. Relevant animal models are desperately needed to address this issue.

Aged↗

PubMed1995

The physiologic and pathologic roles of Tamm-Horsfall glycoprotein in urinary system.

Tamm-Horsfall glycoprotein (THG), a unique renal glycoprotein, is synthesized exclusively by the epithelial cells of the thick ascending loop of Henle and early segment of distal convoluted tubules. The protein is the primary constituent of urinary hyaline cast. The aggregation and gel formation of THG in response to increasing concentrations of electrolytes and low pH within physiologic ranges may affect the permeability of water in this segment. The dual effect of THG on mononuclear cells renders the molecule to become a potent immunomodulator. The cytokine-binding activity of THG lets the kidney an important tissue for cytokine catabolism. The aggregation characteristics of THG also plays a role in pathologic states and leads to the persistence of interstitial deposits in several tubulointerstitial diseases. The induction of immune responses to this protein, including urinary tract infection, reflux nephropathy chronic active hepatic damage, elicites immune complex tubulointerstitial nephritis. It is expected that the detection of THG or its antibodies may aid in the diagnosis of renal tubular disorders.

Adjuvants, Immunologic↗

PubMed2001

Production of reactive oxygen species from aggregating proteins implicated in Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases.

The deposition of abnormal protein fibrils is a prominent pathological feature of many different 'protein conformational' diseases, including some important neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), motor neurone disease and the 'prion' dementias. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the beta-amyloid (Abeta), which accumulates in the brain in AD, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown recently that solutions of Abeta liberate readily detectable amounts of hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). We have also obtained similar results with alpha-synuclein, which accumulates in Lewy bodies in PD. Our data suggest that hydrogen peroxide accumulates during Abeta or alpha-synuclein incubation and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, we now support the idea that one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD, PD, and possibly some other protein conformational diseases, could be the direct production of ROS during formation of the abnormal protein aggregates. This hypothesis suggests a novel approach to the therapy of this group of diseases.

Alzheimer Disease↗

PubMed1998

Aggregation of N-terminal huntingtin is dependent on the length of its glutamine repeats.

Huntington's disease (HD) is caused by expansion of a glutamine repeat in huntingtin. Mutant huntingtin contains 36-55 repeats in adult HD patients and >60 repeats in juvenile HD patients. An N-terminal fragment of mutant huntingtin forms aggregates in neuronal nuclei in the brains of transgenic mice and HD patients. Aggregation of expanded polyglutamine is thought to be a common pathological mechanism in HD and other glutamine repeat diseases. It is not clear how the length of the repeats is correlated with formation of protein aggregates. By expressing a series of huntingtin constructs encoding various glutamine repeats (23-150 units) in cultured cells we observed N-terminal fragments of huntingtin (amino acids 1-67 and 1-212), but not full-length huntingtins, with glutamine repeats >/=66 units formed protein aggregates. Huntingtin aggregation was not induced when the repeat was </=49 units and was markedly promoted by very long repeats >/=120 units. This study suggests that various N-terminal fragments of mutant huntingtin can form aggregates and that aggregation is prompted by lengthening the glutamine repeat.

Animals↗

PubMed1999

Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice.

Huntington disease (HD), an autosomal dominant, progressive neurodegenerative disorder, is caused by an expanded CAG repeat sequence leading to an increase in the number of glutamine residues in the encoded protein. The normal CAG repeat range is 5-36, whereas 38 or more repeats are found in the diseased state; the severity of disease is roughly proportional to the number of CAG repeats. HD shows anticipation, in which subsequent generations display earlier disease onsets due to intergenerational repeat expansion. For longer repeat lengths, somatic instability of the repeat size has been observed both in human cases at autopsy and in transgenic mouse models containing either a genomic fragment of human HD exon 1 (ref. 9) or an expanded repeat inserted into the endogenous mouse gene Hdh (ref. 10). With increasing repeat number, the protein changes conformation and becomes increasingly prone to aggregation, suggesting important functional correlations between repeat length and pathology. Because dinucleotide repeat instability is known to increase when the mismatch repair enzyme MSH2 is missing, we examined instability of the HD CAG repeat by crossing transgenic mice carrying exon 1 of human HD (ref. 16) with Msh2-/- mice. Our results show that Msh2 is required for somatic instability of the CAG repeat.

Animals↗

PubMedDate not supplied

Analysis of the two p97/VCP/Cdc48p proteins of Caenorhabditis elegans and their suppression of polyglutamine-induced protein aggregation.

A class of inherited neurodegenerative diseases including Huntington's disease is caused by polyglutamine (polyQ) expansion in the responsible proteins. Pathology is typically associated with polyQ expansions of greater than 40 residues, and the longer the length of the expansion, the earlier the onset of disease. It has been reported that p97/VCP/Cdc48p, a member of AAA family of proteins, can bind to longer polyQ tracts. In Caenorhabditis elegans, two p97/VCP/Cdc48p homologues, C41C4.8 and C06A1.1, have been identified. Our results indicate that these p97/VCP/Cdc48p homologues have essential but redundant functions in C. elegans. To provide a model system for investigating the molecular basis of pathogenesis, we have expressed polyQ expansions fused to green fluorescent protein in the body wall muscle cells of C. elegans. When the repeats are longer than 40, discrete cytoplasmic aggregates are formed and these appear at an early stage of embryogenesis. The formation of aggregates was partially suppressed by co-expression of either C41C4.8 or C06A1.1. These results suggest that these p97/VCP/Cdc48p homologues, AAA chaperones, may play a protective role in polyQ aggregation.

Adenosine Triphosphatases↗

PubMed2004

Irreversible formation of intermediate BSA oligomers requires and induces conformational changes.

Understanding the relation between protein conformational changes and aggregation, and the physical mechanisms leading to such processes, is of primary importance, due to its direct relation to a vast class of severe pathologies. Growing evidence also suggests that oligomeric intermediates, which may occur early in the aggregation pathway, can be themselves pathogenic. The possible cytotoxicity of oligomers of non-disease-associated proteins adds generality to such suggestion and to the interest of studies of oligomer formation. Here we study the early stages of aggregation of Bovine Serum Albumin (BSA), a non pathogenic protein which has proved to be a useful model system. Dynamic light scattering and circular dichroism measurements in kinetic experiments following step-wise temperature rises, show that the "intermediate" form, which initiates large-scale aggregation, is the result of structural and conformational changes and concurrent formation of oligomers, of average size in the range of 100-200 A. Two distinct thresholds are observed. Beyond the first one oligomerization starts and causes partial irreversibility of conformational changes. Beyond the second threshold, additional secondary structural changes occurring in proteins being recruited progress on the same time scale of oligomerization. The concurrent behavior causes a mutual stabilization of oligomerization, and of structural and conformational changes, evidenced by a progressive increase of their irreversibility. This process interaction appears to be pivotal in producing irreversible oligomers.

Animals↗

PubMed2001

Genetics of Parkinson's disease.

Over the past few years, several genes for monogenically inherited forms of Parkinson's disease (PD) have been mapped and/or cloned. In a small number of families with autosomal dominant inheritance and typical Lewy-body pathology, mutations have been identified in the gene for alpha-synuclein. Aggregation of this protein in Lewy-bodies may be a crucial step in the molecular pathogenesis of familial and sporadic PD. On the other hand, mutations in the parkin gene cause autosomal recessive parkinsonism of early onset. In this form of PD, nigral degeneration is not accompanied by Lewy-body formation. Parkin-mutations appear to be a common cause of PD in patients with very early onset. Parkin has been implicated in the cellular protein degradation pathways, as it has been shown that it functions as a ubiquitin ligase. The potential importance of this pathway is also highlighted by the finding of a mutation in the gene for ubiquitin C-terminal hydrolase L1 in another small family with PD. Other loci have been mapped to chromosome 2p and 4p, respectively, in a small number of families with dominantly inherited PD, but those genes have not yet been identified. These findings prove that there are several genetically distinct forms of PD that can be caused by mutations in single genes. On the other hand, there is at present no direct evidence that any of these genes have a direct role in the aetiology of the common sporadic form of PD. Epidemiological, case control, and twin studies, although supporting a genetic contribution to the development of PD, all suggest a clear familial clustering only in a minority of cases. It is therefore widely believed that a combination of interacting genetic and environmental causes may be responsible in this majority of PD-cases. However, studies of gene-environment interactions have not yet produced any convincing results. Nevertheless, the elucidation of the molecular sequence of events leading to nigral degeneration in clearly inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.

Chromosome Mapping↗

PubMed2002

Hassles with taking out the garbage: aggravating aggresomes.

Diverse human diseases ranging from amyloidosis to neurodegenerative diseases are now recognized as 'conformational diseases' caused by protein misfolding and protein aggregation. Misfolded and aggregated proteins are usually handled in the cell through chaperone-mediated refolding, or when that is impossible, destroyed by proteasomal degradation. Recent evidence suggests that cells might have evolved a third pathway that involves the sequestration of aggregated proteins into specialized 'holding stations' called aggresomes. The aggresomal pathway provides a mechanism by which aggregated proteins form particulate (approximately 200 nm) mini-aggregates that are transported on microtubules (MTs) towards the MT organizing center (MTOC) by a process mediated by the minus-end motor protein dynein. Once at the MTOC, the individual particles pack into a single, usually spherical aggresome (1-3 microm) that surrounds the MTOC. Aggresomes are dynamic: they recruit various chaperones and proteasomes, presumably to aid in the disposal of the aggregated proteins. In addition, the formation of an aggresome is likely to activate the autophagic clearance mechanism that terminates in lysosomal degradation. Hence, the aggresome pathway may provide a novel system to deliver aggregated proteins from the cytoplasm to lysosomes for degradation. Although it is clear that many pathological states correlate with the formation of aggresomes, their causal relationships remain hotly debated. Here, we describe the current state of our knowledge of the aggresome pathway and outline the open questions that provide the focus of current research.

Cytoskeleton↗

PubMed1997

Amyloidosis: a review of recent diagnostic and therapeutic developments.

Amyloid deposition is associated with a diverse range of disorders that includes Alzheimer's disease, type II diabetes mellitus and dialysis arthropathy. Although less common, systemic AA and AL amyloidosis remain important because effective treatments have increasingly become available. The pathology in all forms of amyloidosis involves the extracellular deposition of protein as characteristic fibrillar aggregates which interfere with tissue structure and function. Amyloid fibrils are derived from different unrelated proteins in the different forms of the disease but share many common properties, including the capacity to bind the normal plasma protein serum amyloid P component (SAP). This is the basis for our development of radiolabelled SAP as a nuclear medicine tracer for the diagnosis and quantitative monitoring of amyloid. Serial studies have shown that the deposits are far from inert but are actually turned over quite rapidly in many patients. The treatment of amyloidosis involves supportive measures whilst every effort is made to reduce the supply of the respective fibril precursor protein. Under favourable circumstances further amyloid deposition will be prevented. existing deposits will regress and improvement of organ function will occur. Since this strategy is not always possible or may fail, new approaches to inhibit fibril formation and promote regression of amyloid are being pursued.

Amyloid↗

PubMed2004

[Advances in molecular biology and clinical study of amyloid precursor protein for Alzheimer's disease].

Alzheimer's disease (AD) is the most common cause of dementia in elderly population. There are two hallmark pathological lesions: the intracellular neurofibrillary tangles (NFTs) and the extracellular amyloid deposits in the senile plaques (SP). The NFTs are aggregates of hyperphosphorylated microtubule Tau protein. The amyloid deposits in the SP are the beta-amyloid (Abeta) peptides-Abeta40 and Abeta42. The Abeta peptides are derived from the amyloid precursor protein (APP) which is considered very important for the AD pathogenesis. In recent years, studies have focused on understanding the generation of Abeta peptides by the alpha-, beta- and gamma- secretase activity on APP, as cause and progression of both familial and sporadic AD (FAD and SAD). This review covers the trafficking and processing of APP, the amyloid cascade hypothesis in AD pathogenesis, the mutations in the genes encoding APP, PS1 and PS2 of early-onset and late-onset AD. The risk factor apolipoprotein E (ApoE) for AD and therapeutic anti-beta-amyloid vaccination strategies for prevention of AD are also discussed.

Alzheimer Disease↗

PubMedDate not supplied

Protein misfolding disorders: pathogenesis and intervention.

Newly synthesized proteins in the living cell must go through a folding process to attain their functional structure. To achieve this in an efficient fashion, all organisms, including humans, have evolved a large set of molecular chaperones that assist the folding as well as the maintenance of the functional structure of cellular proteins. Aberrant proteins, the result of production errors, inherited or acquired amino acid substitutions or damage, especially oxidative modifications, can in many cases not fold correctly and will be trapped in misfolded conformations. To rid the cell of misfolded proteins, the living cell contains a large number of intracellular proteases, e.g. the proteasome, which together with the chaperones comprise the cellular protein quality control systems. Many inherited disorders due to amino acid substitutions exhibit loss-of-function pathogenesis because the aberrant protein is eliminated by one of the protein quality control systems. Examples are cystic fibrosis and phenylketonuria. However, not all aberrant proteins can be eliminated and the misfolded protein may accumulate and form toxic oligomeric and/or aggregated inclusions. In this case the loss of function may be accompanied by a gain-of-function pathogenesis, which in many cases determines the pathological and clinical features. Examples are Parkinson and Huntington diseases. Although a number of strategies have been tried to decrease the amounts of accumulated and aggregated proteins, a likely future strategy seems to be the use of chemical or pharmacological chaperones with specific effects on the misfolded protein in question. Positive examples are enzyme enhancement in a number of lysosomal disorders.

Animals↗

PubMed2000

Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias.

We have studied biochemical and structural parameters of several missense and deletion mutants of tau protein (G272V, N279K, DeltaK280, P301L, V337M, R406W) found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The mutant proteins were expressed on the basis of both full-length tau (htau40) and constructs derived from the repeat domain. They were analyzed with respect to the capacity to enhance microtubule assembly, binding of tau to microtubules, secondary structure content, and aggregation into Alzheimer-like paired helical or straight filaments. We find that the mutations cause a moderate decrease in microtubule interactions and stabilization, and they show no gross structural changes compared with the natively unfolded conformation of the wild-type protein, but the aggregation into PHFs is strongly enhanced, particularly for the mutants DeltaK280 and P301L. This gain of pathological aggregation would be consistent with the autosomal dominant nature of the disease.

Actin Cytoskeleton↗

PubMed2003

ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization.

Many point mutations in human Cu,Zn superoxide dismutase (SOD) cause familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder in heterozygotes. Here we show that these mutations cluster in protein regions influencing architectural integrity. Furthermore, crystal structures of SOD wild-type and FALS mutant H43R proteins uncover resulting local framework defects. Characterizations of beta-barrel (H43R) and dimer interface (A4V) FALS mutants reveal reduced stability and drastically increased aggregation propensity. Moreover, electron and atomic force microscopy indicate that these defects promote the formation of filamentous aggregates. The filaments resemble those seen in neurons of FALS patients and bind both Congo red and thioflavin T, suggesting the presence of amyloid-like, stacked beta-sheet interactions. These results support free-cysteine-independent aggregation of FALS mutant SOD as an integral part of FALS pathology. They furthermore provide a molecular basis for the single FALS disease phenotype resulting from mutations of diverse side-chains throughout the protein: many FALS mutations reduce structural integrity, lowering the energy barrier for fibrous aggregation.

Amyotrophic Lateral Sclerosis↗

PubMed2003

Pathogenesis of polyglutamine disorders: aggregation revisited.

Expansion of CAG trinucleotide repeats coding for polyglutamine in unrelated proteins causes at least nine late-onset progressive neurodegenerative disorders, including Huntington's disease and a number of spinocerebellar ataxias. Expanded polyglutamine provokes a dominant gain-of-function neurotoxicity, regardless of the specific protein context within which it resides. Nevertheless, the protein context does modulate polyglutamine toxicity, as evidenced by the distinct clinical and pathological features of the various disorders. Importantly, polyglutamine toxicity might derive from its ability to aggregate. Indeed, aggregation probably underlies some defining attributes of the polyglutamine disorders, such as their late onset, progressive nature, and the dependence of onset age on polyglutamine length. However, the central role of aggregation in polyglutamine pathogenesis has been challenged by several studies, which instead argued that the soluble form of the disease proteins is responsible for neuronal damage. Thus, the question whether polyglutamine aggregates are deleterious, harmless or protective remains the most passionately disputed issue in the study of these diseases. In this review, we attempt to reconcile some of these controversies.

Animals↗

PubMed2005

Surface-induced aggregation of beta amyloid peptide by co-substituted alkanethiol monolayers supported on gold.

The primary pathological characteristic of Alzheimer's disease is the presence in the brain of self-assembled beta amyloid (Abeta) protein fibrils, consisting of 35-43 amino acid residues. The toxicity of the aggregated protein structures has previously been proposed to be related to the interaction of Abeta fibrils with neuronal membranes (phospholipid bilayers). Here, surfaces consisting of self-assembled alkanethiol monolayers with different end groups--supported on Au--are used to test the effect of surface chemistry on the structure and morphology of aggregates formed from an active fragment (Abeta10-35) of the Abeta peptide. The influence of monolayer nature (end group) on the aggregation of Abeta10-35 was examined using reflection-absorption infrared spectroscopy (RAIRS) and scanning force microscopy (SFM). Evaluation of the SFM and RAIRS data reveals the presence of Abeta10-35 protein on the various monolayer surfaces, with the surface protein possessing predominantly beta-sheet and random-coil conformations. Time-dependent studies of the extent of Abeta10-35 aggregation and deposition on the various surfaces and the effect of the monolayers on seeding of Abeta10-35 aggregates in solution are also discussed.

Alkanes↗