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Results for “Protein misfolding”

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At least 19 recordsLinked to original sources

PubMed2004

Conformation-dependent antibodies target diseases of protein misfolding.

Many degenerative diseases are fundamentally associated with aging and the accumulation of misfolded proteins as amyloid fibrils. Although such diseases are associated with different proteins, they share several pathological features. These similarities might be due to underlying commonalities in the pathway of aggregation and the structures of the various aggregation products. Because protein misfolding is thought to be central to the pathological state, it is essential to be able to distinguish such pathological states from native and non-pathological states, especially in vivo or in complex mixtures. Conformation-dependent antibodies that specifically recognize misfolded proteins are proving to be useful tools for examining the mechanisms of amyloid formation and for clarifying the roles of various misfolded states in pathogenesis. The common structures and mechanisms hold promise for the development of broad-spectrum drugs and vaccines that will be effective for the treatment of many of these diseases.

Amyloid↗

PubMed2006

Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration.

Misfolded proteins are associated with several pathological conditions including neurodegeneration. Although some of these abnormally folded proteins result from mutations in genes encoding disease-associated proteins (for example, repeat-expansion diseases), more general mechanisms that lead to misfolded proteins in neurons remain largely unknown. Here we demonstrate that low levels of mischarged transfer RNAs (tRNAs) can lead to an intracellular accumulation of misfolded proteins in neurons. These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response. We report that the mouse sticky mutation, which causes cerebellar Purkinje cell loss and ataxia, is a missense mutation in the editing domain of the alanyl-tRNA synthetase gene that compromises the proofreading activity of this enzyme during aminoacylation of tRNAs. These findings demonstrate that disruption of translational fidelity in terminally differentiated neurons leads to the accumulation of misfolded proteins and cell death, and provide a novel mechanism underlying neurodegeneration.

Acetylation↗

PubMed2005

Theoretical model of prion propagation: a misfolded protein induces misfolding.

There is a hypothesis that dangerous diseases such as bovine spongiform encephalopathy, Creutzfeldt-Jakob, Alzheimer's, fatal familial insomnia, and several others are induced by propagation of wrong or misfolded conformations of some vital proteins. If for some reason the misfolded conformations were acquired by many such protein molecules it might lead to a "conformational" disease of the organism. Here, a theoretical model of the molecular mechanism of such a conformational disease is proposed, in which a metastable (or misfolded) form of a protein induces a similar misfolding of another protein molecule (conformational autocatalysis). First, a number of amino acid sequences composed of 32 aa have been designed that fold rapidly into a well defined native-like alpha-helical conformation. From a large number of such sequences a subset of 14 had a specific feature of their energy landscape, a well defined local energy minimum (higher than the global minimum for the alpha-helical fold) corresponding to beta-type structure. Only one of these 14 sequences exhibited a strong autocatalytic tendency to form a beta-sheet dimer capable of further propagation of protofibril-like structure. Simulations were done by using a reduced, although of high resolution, protein model and the replica exchange Monte Carlo sampling procedure.

Amino Acid Sequence↗

PubMed2001

Protein misfolding and temperature up-shift cause G1 arrest via a common mechanism dependent on heat shock factor in Saccharomycescerevisiae.

Accumulation of misfolded proteins in the cell at high temperature may cause entry into a nonproliferating, heat-shocked state. The imino acid analog azetidine 2-carboxylic acid (AZC) is incorporated into cellular protein competitively with proline and can misfold proteins into which it is incorporated. AZC addition to budding yeast cells at concentrations sufficient to inhibit proliferation selectively activates heat shock factor (HSF). We find that AZC treatment fails to cause accumulation of glycogen and trehalose (Msn2/4-dependent processes) or to induce thermotolerance (a protein kinase C-dependent process). However, AZC-arrested cells can accumulate glycogen and trehalose and can acquire thermotolerance in response to a subsequent heat shock. We find that AZC treatment arrests cells in a viable state and that this arrest is reversible. We find that cells at high temperature or cells deficient in the ubiquitin-conjugating enzymes Ubc4 and Ubc5 are hypersensitive to AZC-induced proliferation arrest. We find that AZC treatment mimics temperature up-shift in arresting cells in G1 and represses expression of CLN1 and CLN2. Mutants with reduced G1 cyclin-Cdc28 activity are hypersensitive to AZC-induced proliferation arrest. Expression of the hyperstable Cln3-2 protein prevents G1 arrest upon AZC treatment and temperature up-shift. Finally, we find that the EXA3-1 mutation, encoding a defective HSF, prevents efficient G1 arrest in response to both temperature up-shift and AZC treatment. We conclude that nontoxic levels of misfolded proteins (induced by AZC treatment or by high temperature) selectively activate HSF, which is required for subsequent G1 arrest.

Azetidinecarboxylic Acid↗

PubMed2004

Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death.

A variety of debilitating diseases including diabetes, Alzheimer's, Huntington's, Parkinson's, and prion-based diseases are linked to stress within the endoplasmic reticulum (ER). Using S. cerevisiae, we sought to determine the relationship between protein misfolding, ER stress, and cell death. In the absence of ERV29, a stress-induced gene required for ER associated degradation (ERAD), misfolded proteins accumulate in the ER leading to persistent ER stress and subsequent cell death. Cells alleviate ER stress through the unfolded protein response (UPR); however, if stress is sustained the UPR contributes to cell death by causing the accumulation of reactive oxygen species (ROS). ROS are generated from two sources: the UPR-regulated oxidative folding machinery in the ER and mitochondria. Our results demonstrate a direct mechanism(s) by which misfolded proteins lead to cellular damage and death.

Cell Death↗

PubMed1997

Protein misfolding in the cell envelope of Escherichia coli: new signaling pathways.

Depending on their cellular localization, misfolded proteins in Escherichia coli trigger two different heat-shock responses. Cytoplasmic proteins induce the 'classical' heat-shock regulon transcribed by the E sigma 32 polymerase. By contrast, misfolding of proteins in the cell envelope induces the newly described E sigma E-dependent regulon. This implies that there is an inducible transduction machinery in the inner membrane. The response to protein misfolding in the cell envelope is a finely tuned system regulated by a cascade of phosphorylation and dephosphorylation reactions.

Bacterial Proteins↗

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↗

PubMed2006

Protein misfolding and human disease.

Protein misfolding is a common event in living cells. In young and healthy cells, the misfolded protein load is disposed of by protein quality control (PQC) systems. In aging cells and in cells from certain individuals with genetic diseases, the load may overwhelm the PQC capacity, resulting in accumulation of misfolded proteins. Dependent on the properties of the protein and the efficiency of the PQC systems, the accumulated protein may be degraded or assembled into toxic oligomers and aggregates. To illustrate this concept, we discuss a number of very different protein misfolding diseases including phenylketonuria, Parkinson's disease, alpha-1-antitrypsin deficiency, familial neurohypophyseal diabetes insipidus, and short-chain acyl-CoA dehydrogenase deficiency. Despite the differences, an emerging paradigm suggests that the cellular effects of protein misfolding provide a common framework that may contribute to the elucidation of the cell pathology and guide intervention and treatment strategies of many genetic and age-dependent diseases.

Aging↗

PubMed2001

Protein misfolding and disease; protein refolding and therapy.

Diverse human disorders, including several neurodegenerative diseases and systemic amyloidosis, are thought to arise from the misfolding and aggregation of an underlying protein. Recent findings strongly support this hypothesis and have increased our understanding of the molecular mechanism of protein conformational disorders. Many questions are still pending, but the data overall suggest that correction of protein misfolding constitutes a viable therapeutic strategy for conformational diseases.

Animals↗

PubMed2005

Amyloid ion channels: a common structural link for protein-misfolding disease.

Protein conformational diseases, including Alzheimer's, Huntington's, and Parkinson's diseases, result from protein misfolding, giving a distinct fibrillar feature termed amyloid. Recent studies show that only the globular (not fibrillar) conformation of amyloid proteins is sufficient to induce cellular pathophysiology. However, the 3D structural conformations of these globular structures, a key missing link in designing effective prevention and treatment, remain undefined as of yet. By using atomic force microscopy, circular dichroism, gel electrophoresis, and electrophysiological recordings, we show here that an array of amyloid molecules, including amyloid-beta(1-40), alpha-synuclein, ABri, ADan, serum amyloid A, and amylin undergo supramolecular conformational change. In reconstituted membranes, they form morphologically compatible ion-channel-like structures and elicit single ion-channel currents. These ion channels would destabilize cellular ionic homeostasis and hence induce cell pathophysiology and degeneration in amyloid diseases.

Amyloid↗

PubMed2004

A membrane protein required for dislocation of misfolded proteins from the ER.

After insertion into the endoplasmic reticulum (ER), proteins that fail to fold there are destroyed. Through a process termed dislocation such misfolded proteins arrive in the cytosol, where ubiquitination, deglycosylation and finally proteasomal proteolysis dispense with the unwanted polypeptides. The machinery involved in the extraction of misfolded proteins from the ER is poorly defined. The human cytomegalovirus-encoded glycoproteins US2 and US11 catalyse the dislocation of class I major histocompatibility complex (MHC) products, resulting in their rapid degradation. Here we show that US11 uses its transmembrane domain to recruit class I MHC products to a human homologue of yeast Der1p, a protein essential for the degradation of a subset of misfolded ER proteins. We show that this protein, Derlin-1, is essential for the degradation of class I MHC molecules catalysed by US11, but not by US2. We conclude that Derlin-1 is an important factor for the extraction of certain aberrantly folded proteins from the mammalian ER.

Amino Acid Sequence↗

PubMed1997

Signal transduction pathways in response to protein misfolding in the extracytoplasmic compartments of E. coli: role of two new phosphoprotein phosphatases PrpA and PrpB.

It is now well established that the sigmaE regulon of Escherichia coli is induced by misfolding of proteins in the periplasm and the outer membrane. htrA belongs to this regulon and encodes a periplasmic protease involved in the degradation of misfolded proteins. htrA transcription is also under the positive control of a two component signal transduction system CpxR CpxA. Closer examination of the putative signal transduction pathway modulating htrA transcription has led us to the identification of two new genes. Biochemical and genetic evidence shows that these two genes encode two phosphoprotein phosphatases, designated PrpA and PrpB. These are the first examples of typical serine/threonine and tyrosine phosphatases described in E. coli. PrpA and PrpB are involved in signaling protein misfolding via the CpxR CpxA transducing system. In addition, both PrpA and PrpB modulate the phosphorylated status of some other phosphoproteins in E. coli. Finally, we show that PrpA is a heat shock protein.

Amino Acid Sequence↗

PubMed2004

High pressure, an alternative approach to understand protein misfolding diseases.

Protein folding is essential for the flow of genetic information to biological activity. A failure in this process can result in disease, by causing cell damage and sometimes death. The misfolding of proteins often induces their aggregation, initiating the fibril formation seen in a range of human and animal diseases. Because misfolding and aggregation are of fundamental importance in vivo, there is currently great interest in understanding their mechanisms. To gain insight into the folding and unfolding processes of proteins, for nearly a century, an original biophysical approach has been successfully used: the application of high hydrostatic pressure combined with various spectroscopic and kinetic techniques. Because high pressure provides new insight into protein structure and folding which cannot be obtained by other techniques, the conformations of pressure-induced unfolding intermediates and species involved in the initial states of aggregation of proteins associated with specific diseases are currently being investigated. Our contention is that by exploring folding kinetics, misfolding pathways and stability under pressure, it will be possible to understand the mechanisms of amyloidogenesis, with the ultimate goal to design therapeutic strategies to prevent progression of the disease.

Amyloid↗

PubMed2006

S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.

Stress proteins located in the cytosol or endoplasmic reticulum (ER) maintain cell homeostasis and afford tolerance to severe insults. In neurodegenerative diseases, several chaperones ameliorate the accumulation of misfolded proteins triggered by oxidative or nitrosative stress, or of mutated gene products. Although severe ER stress can induce apoptosis, the ER withstands relatively mild insults through the expression of stress proteins or chaperones such as glucose-regulated protein (GRP) and protein-disulphide isomerase (PDI), which assist in the maturation and transport of unfolded secretory proteins. PDI catalyses thiol-disulphide exchange, thus facilitating disulphide bond formation and rearrangement reactions. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin. During neurodegenerative disorders and cerebral ischaemia, the accumulation of immature and denatured proteins results in ER dysfunction, but the upregulation of PDI represents an adaptive response to protect neuronal cells. Here we show, in brains manifesting sporadic Parkinson's or Alzheimer's disease, that PDI is S-nitrosylated, a reaction transferring a nitric oxide (NO) group to a critical cysteine thiol to affect protein function. NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. S-nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress, misfolded proteins or proteasome inhibition. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the S-nitrosylation of PDI.

Alzheimer Disease↗

PubMed1998

A pancreas-specific glycosylated protein disulphide-isomerase binds to misfolded proteins and peptides with an interaction inhibited by oestrogens.

Using a cross-linking approach, we have demonstrated that radiolabeled model peptides or misfolded proteins specifically interact in vitro with two different luminal proteins in a crude extract from sheep pancreas microsomes. One of the proteins was identified as protein disulphide-isomerase (PDI), the other one was a related protein (PDIp). We have shown that PDIp was expressed exclusively in the pancreas. Interspecies conservation of PDIp was confirmed and, unlike other members of the PDI family, PDIp from various sources was found to be a glycoprotein. PDIp interacted with peptides and also a misfolded protein, but not with native proteins, suggesting that it might act as a molecular chaperone. The initial binding process was independent of the presence of Cys residues in the probed peptides. Certain oestrogens strongly inhibited the interaction between peptides and PDIp, with 17beta-oestradiol being the most potent inhibitor.

Animals↗

PubMed1998

Aggresomes: a cellular response to misfolded proteins.

Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein and how they are delivered to cytoplasmic inclusions are not known. We have investigated the intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR), an inefficiently folded integral membrane protein which is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells led to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy with immunogold labeling, we demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which we have termed the aggresome. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevented the degradation of unassembled presenilin-1 molecules leading to their aggregation and deposition in aggresomes. These data lead us to propose that aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.

Animals↗

PubMed2003

The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.

The efficient clearance of cytotoxic misfolded protein aggregates is critical for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-associated deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.

Animals↗

PubMed2005

Membrane permeabilization: a common mechanism in protein-misfolding diseases.

Protein aggregation--and, more specifically, amyloid fibril formation--has been implicated as a primary cause of neurodegeneration in Alzheimer's disease, Parkinson's disease, and related disorders, but the mechanism by which this process triggers neuronal death is unknown. Mounting evidence from in vitro studies, cell culture, and animal models of these diseases supports the hypothesis that a structural intermediate on the pathway to fibril formation, rather than amyloid fibrils themselves, may be the pathogenic species. Characterization of these intermediates in solution or upon interactions with membranes indicate that these intermediates form pores and suggests that neurons could be killed by unregulated membrane permeabilization caused by such "amyloid pores."

Cell Membrane Permeability↗