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At least 19 recordsLinked to original sources
PubMed1994

Cells overexpressing Hsp27 show accelerated recovery from heat-induced nuclear protein aggregation.

Protein denaturation/aggregation upon cell exposure to heat shock is a likely cause of cell death. In the nucleus, protein aggregation has often been correlated to inhibition of nuclear located processes and heat-induced cell killing. In Chinese hamster O23 cells made thermotolerant by a prior heating (20'44 degrees C + 10h 37 degrees C) which induces the whole spectrum of heat shock proteins (hsps), the extent of nuclear protein aggregation during heat shock is reduced and the rate of recovery from aggregation after heat shock is enhanced. In contrast, a heat resistant Chinese hamster cell line overexpressing only hsp27 shows an unaltered sensitivity to formation of nuclear protein aggregates by heat, but shows the same enhanced rate of recovery from nuclear protein aggregation as thermotolerant cells. This suggests that accelerated recovery of protein aggregation could be partly responsible for hsp27-mediated thermoprotection.

Animals↗
PubMed2001

Protein aggregation.

Protein aggregation occurs in vivo as a result of improper folding or misfolding. Diverse diseases arise from protein misfolding and are now grouped under the term "protein conformational diseases", including most of the neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, the prion encephalopathies and Huntington's disease, as well as cystic fibrosis, sickle cell anemia and other less common conditions. The hallmark event in these diseases is a change in the secondary and/or tertiary structure of a normal, functional protein, leading to the formation of protein aggregates with various supramolecular organizations. In most cases the aggregates are organized in structurally well-defined fibrils forming amyloid deposits. The crucial feature of the amyloidogenic proteins is their structural instability induced either by mutations, post-translational modifications, or local conditions, such as pH, temperature, and co-solutes. The conformational change may promote the disease either by gain of a toxic activity or by the lack of biological function of the natively folded protein. As different molecular mechanisms are involved in the formation of the various forms of protein aggregates, the laboratory diagnostic approach remains frequently elusive.

Amyloidosis↗
PubMed1991

Protein aggregation in vitro and in vivo: a quantitative model of the kinetic competition between folding and aggregation.

Protein aggregation is frequently observed as a major side-reaction of protein folding. We present quantitative models explaining the formation of aggregates during protein folding in vitro and in vivo on the basis of a kinetic competition between correct folding and aggregation reactions. Both models are in good agreement with experimental data. The model implies that, in vitro, the yield of native protein obtained upon refolding is determined by the rates of the competing first order folding and second order aggregation reactions. Therefore, a high protein concentrations aggregation dominates over folding and leads to the formation of insoluble protein. For in vivo protein synthesis, the model shows that the yield of native protein is only dependent on the rate of folding, on the rate of aggregation and on the rate of protein synthesis. In the cell, several mechanisms, including "folding helpers" seem to have evolved, which influence these processes and thereby prevent unproductive side reactions.

Kinetics↗
PubMed2006

Protein particulates: another generic form of protein aggregation?

Protein aggregation is a problem with a multitude of consequences, ranging from affecting protein expression to its implication in many diseases. Of recent interest is the specific form of aggregation leading to the formation of amyloid fibrils, structures associated with diseases such as Alzheimer's disease. The ability to form amyloid fibrils is now regarded as a property generic to all polypeptide chains. Here we show that around the isoelectric point a different generic form of aggregation can also occur by studying seven widely different, nonrelated proteins that are also all known to form amyloid fibrils. Under these conditions gels consisting of relatively monodisperse spherical particulates are formed. Although these gels have been described before for beta-lactoglobulin, our results suggest that the formation of particulates in the regime where charge on the molecules is minimal is a common property of all proteins. Because the proteins used here also form amyloid fibrils, we further propose that protein misfolding into clearly defined aggregates is a generic process whose outcome depends solely on the general properties of the state the protein is in when aggregation occurs, rather than the specific amino acid sequence. Thus under conditions of high net charge, amyloid fibrils form, whereas under conditions of low net charge, particulates form. This observation furthermore suggests that the rules of soft matter physics apply to these systems.

Amyloid↗
PubMed2001

Only the reduced conformer of alpha-lactalbumin is inducible to aggregation by protein aggregates.

Reduced apo-alpha-lactalbumin (r-LA) in the pre-molten globule state is soluble in neutral and reduced buffer at 25 degrees C but becomes aggregated when aggregates of various proteins are added. However, protein aggregates do not induce the aggregation of apo-alpha-lactalbumin in the molten globule state. The presence of the molecular chaperone protein disulfide isomerase or the "chemical chaperone" polyethyleneglycol inhibits the induced aggregation. Native proteins, aggregation-free folding intermediates, and soluble aggregates do not induce the aggregation. The interaction between r-LA and protein aggregates is hydrophobic in nature. These findings suggest that pre-molten globule state of LA is the target not only for chaperones but also for protein aggregates.

Animals↗
PubMed2004

Neurodegenerative aspects of protein aggregation.

Protein aggregation and amyloid fibril deposits are characteristic features of more than twenty pathologic conditions characterized by plaque deposition in the central nervous system. Recent studies point out relationships between protein misfolding and numerous serious diseases. Despite different origins (sporadic, familial or transmissible), they are sometimes called conformational diseases to emphasize aberrant conformations as the putative cause of deposits that precede or accompany the clinical manifestation of the disease. Neurological disorders such as Alzheimer's disease (AD), Prion disorders (PrD), Parkinson's disease (PD), and Huntington's disease (HD) are the most typical examples of protein-based dementias, characterized by protein conformational transitions (alpha-helix/random coil to beta-sheet) that cause aggregation followed by fibrillization. Although it is very tempting to postulate a common mechanism of toxicity based on conformational and structural analogies, it should be noted that the factors responsible for conformational transition, oligomerization, aggregation, and plaque formation, are still subject of speculation and additional data is required to test the amyloid fibril hypothesis.

Alzheimer Disease↗
PubMed2005

Protein aggregation, metals and oxidative stress in neurodegenerative diseases.

There is clear evidence implicating oxidative stress in the pathology of many different neurodegenerative diseases. ROS (reactive oxygen species) are the primary mediators of oxidative stress and many of the aggregating proteins and peptides associated with neurodegenerative disease can generate hydrogen peroxide, a key ROS, apparently through interactions with redox-active metal ions. Our recent results suggest that ROS are generated during the very early stages of protein aggregation, when protofibrils or soluble oligomers are present, but in the absence of mature amyloid fibrils. The generation of ROS during early-stage protein aggregation may be a common, fundamental molecular mechanism underlying the pathogenesis of oxidative damage, neurodegeneration and cell death in several different neurodegenerative diseases. Drugs that specifically target this process could be useful in the future therapy of these diseases.

Humans↗
PubMed2001

Aggregated proteins accelerate but do not increase the aggregation of D-glyceraldehyde-3-phosphate dehydrogenase. Specificity of protein aggregation.

The effect of protein aggregates on the aggregation of D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) during unfolding and refolding has been studied. The aggregation of GAPDH follows a sigmoid course. The presence of protein aggregates increases the aggregation rate during unfolding and refolding of GAPDH but does not change the extent of aggregation and the final renaturation yield. It is suggested that protein aggregates function as seeds for aggregation via hydrophobic interaction with only GAPDH folding intermediates destined to aggregate and do not affect the distribution between pathways leading to correct folding and aggregation. Moreover, two different proteins do not interfere with each other during their simultaneous refolding together in a buffer. These findings provide insight into a mechanism by which cells prevent protein folding against the interference from aggregation of other proteins.

Animals↗
PubMed2005

Opinion: What is the role of protein aggregation in neurodegeneration?

Neurodegenerative diseases typically involve deposits of inclusion bodies that contain abnormal aggregated proteins. Therefore, it has been suggested that protein aggregation is pathogenic. However, several lines of evidence indicate that inclusion bodies are not the main cause of toxicity, and probably represent a cellular protective response. Aggregation is a complex multi-step process of protein conformational change and accretion. The early species in this process might be most toxic, perhaps through the exposure of buried moieties such as main chain NH and CO groups that could serve as hydrogen bond donors or acceptors in abnormal interactions with other cellular proteins. This model implies that the pathogenesis of diverse neurodegenerative diseases arises by common mechanisms, and might yield common therapeutic targets.

Humans↗
PubMedDate not supplied

Heat shock causes protein aggregation and reduced protein solubility at the centrosome and other cytoplasmic locations.

Heat shock markedly inhibited centrosome staining by antisera raised against the two centrosome-specific proteins, pericentrin and gamma tubulin. The inhibition of anti-pericentrin binding was measured by fluorescence imaging. Heat had the greatest effect on intact cells, followed in sensitivity by centrosomes attached to their companion nucleus, with purified centrosomes being least sensitive. The centrosomal content of pericentrin was measured by immunoprecipitation followed by western blotting. Heat caused the amount of pericentrin in the centrosomal fraction to increase, suggesting that pericentrin did not leave the centrosome during heat shock. Furthermore, the pericentrin of the centrosomal fraction became less soluble after heat shock, and could only be solubilized by the most denaturing condition of boiling in 0.1% SDS. Immunoelectron microscopy revealed a heat-induced increase in the electron-dense material comprising the pericentriolar material (PCM), consistent with protein aggregation. Lastly, in heated cells immunoelectron microscopy demonstrated an increase in the binding of heat shock protein 70 (HSP70) to numerous locations throughout the cytoplasm. These data suggest that heat shock reduces the solubility of centrosomal and other cytoplasmic proteins, most likely through protein aggregation.

Animals↗
PubMed2005

Protein denaturation and aggregation: Cellular responses to denatured and aggregated proteins.

Protein aggregation is a prominent feature of many neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's diseases, as well as spongiform encephalopathies and systemic amyloidoses. These diseases are sometimes called protein misfolding diseases, but the latter term begs the question of what is the "folded" state of proteins for which normal structure and function are unknown. Amyloid consists of linear, unbranched protein or peptide fibrils of approximately 100 A diameter. These fibrils are composed of a wide variety of proteins that have no sequence homology, and no similarity in three-dimensional structures--and yet, as fibrils, they share a common secondary structure, the beta-sheet. Because of the prominence of amyloid deposits in many of these diseases, much effort has gone into elucidation of fibril structure. Recent advances in solid-state NMR spectroscopy and other biophysical techniques have led to the partial elucidation of fibril structure. Surprisingly at the time, for beta-amyloid, a set of 39-43-amino-acid peptides believed to play a pathogenic role in Alzheimer's disease, the beta-sheets are parallel with all amino acids of the sheets in-register. Since the time of those observations, however, it has become clear that there is no universal structure for amyloid fibrils. While many of the amyloid fibrils described thus far have a parallel beta-sheet structure, some have antiparallel beta-sheets, and other, more subtle structural differences among amyloids exist as well. Amyloids demonstrate conformational plasticity, the ability to adopt more than one stable tertiary fold. Conformational plasticity could account for "strain" differences in prions, and for the fact that a single polypeptide can form different fibril types with conformational differences at the atomic level. More recent data now indicate that the fibrils may not be the most potent or proximate mediators of cyto- and neurotoxicity. This damage is not confined to cell death, but also includes more subtle forms of damage, such as disruption of synaptic plasticity in the central nervous system. Rather than fibrils, prefibrillar aggregates, variously called "micelles," "protofibrils," or ADDLs (beta-amyloid-derived diffusible ligands in the case of beta-amyloid) may be the more proximate mediators of cell damage. These are soluble oligomers of aggregating peptides or proteins, but their structure is very challenging to study, because they are generally difficult to obtain in large enough quantities for high-resolution structural techniques, and they are temporally unstable, rapidly changing into more mature, and eventually fibrillar forms. Consequently, the mechanisms by which they disrupt cellular function are also not well understood. Nevertheless, three broad, overlapping, nonexclusive sets of mechanisms have been proposed as responsible for the cellular damage caused by soluble, oligomeric protein aggregates. These are: (1) disruption of cell membranes and their functions [e.g., by inserting into membranes and disrupting normal ion gradients]; (2) inactivation of normally folded, functional proteins [e.g., by sequestering or localizing transcription factors to the wrong cellular compartment]; and (3) "gumming up the works," by binding to and inactivating components of the quality-control system of cells, such as the proteasome or chaperone proteins.

Amino Acid Sequence↗
PubMed2005

Protein aggregate myopathies.

Protein aggregate myopathies (PAM) are an emerging group of muscle diseases characterized by structural abnormalities. Protein aggregate myopathies are marked by the aggregation of intrinsic proteins within muscle fibers and fall into four major groups or conditions: (1) desmin-related myopathies (DRM) that include desminopathies, a-B crystallinopathies, selenoproteinopathies caused by mutations in the, a-B crystallin and selenoprotein N1 genes, (2) hereditary inclusion body myopathies, several of which have been linked to different chromosomal gene loci, but with as yet unidentified protein product, (3) actinopathies marked by mutations in the sarcomeric ACTA1 gene, and (4) myosinopathy marked by a mutation in the MYH-7 gene. While PAM forms 1 and 2 are probably based on impaired extralysosomal protein degradation, resulting in the accumulation of numerous and diverse proteins (in familial types in addition to respective mutant proteins), PAM forms 3 and 4 may represent anabolic or developmental defects because of preservation of sarcomeres outside of the actin and myosin aggregates and dearth or absence of other proteins in these actin or myosin aggregates, respectively. The pathogenetic principles governing protein aggregation within muscle fibers and subsequent structural sarcomeres are still largely unknown in both the putative catabolic and anabolic forms of PAM. Presence of inclusions and their protein composition in other congenital myopathies such as reducing bodies, cylindrical spirals, tubular aggregates and others await clarification. The hitherto described PAMs were first identified by immunohistochemistry of proteins and subsequently by molecular analysis of their genes.

Actins↗
PubMed2000

Aggresomes, inclusion bodies and protein aggregation.

Intracellular and extracellular accumulation of aggregated protein are linked to many diseases, including ageing-related neurodegeneration and systemic amyloidosis. Cells avoid accumulating potentially toxic aggregates by mechanisms including the suppression of aggregate formation by molecular chaperones and the degradation of misfolded proteins by proteasomes. Once formed, aggregates tend to be refractory to proteolysis and to accumulate in inclusion bodies. This accumulation has been assumed to be a diffusion-limited process, but recent studies suggest that, in animal cells, aggregated proteins are specifically delivered to inclusion bodies by dynein-dependent retrograde transport on microtubules. This microtubule-dependent inclusion body is called an aggresome.

Animals↗
PubMed1980

The specificity of uptake of model immune complexes and other protein aggregates by the murine reticuloendothelial system.

We have studied the selectivity of the murine reticuloendothelial system in recognizing and removing from the blood model immune complexes and several aggregated proteins. Although both IgG anti-DNP model immune complexes and micro-aggregated albumin exhibited rapid hepatic uptake, which is saturable, they did not cross-inhibit each other. Aggregates of ovalbumin, a glycoprotein rich in mannose (a sugar recognized by Kupffer cells), had no effect on the uptake by the liver of either IgG immune complexes or micro-aggregated albumin. The finding that transferrin aggregates were not taken up by the liver at all suggests that aggregation alone is not sufficient to overcome the lack of a specific hepatic receptor for that protein. Thus, several mechanisms exist whereby aggregated proteins can be cleared from the blood by the reticuloendothelial system, an observation consistent with the selective failure of reticuloendothelial function found in several human diseases.

Animals↗
PubMed2003

Physical stability of proteins in aqueous solution: mechanism and driving forces in nonnative protein aggregation.

Irreversible protein aggregation is problematic in the biotechnology industry, where aggregation is encountered throughout the lifetime of a therapeutic protein, including during refolding, purification, sterilization, shipping, and storage processes. The purpose of the current review is to provide a fundamental understanding of the mechanisms by which proteins aggregate and by which varying solution conditions, such as temperature, pH, salt type, salt concentration, cosolutes, preservatives, and surfactants, affect this process.

Drug Stability↗
PubMed2006

Sorbitol crystallization can lead to protein aggregation in frozen protein formulations.

PURPOSE: This work examines the cause of aggregation of an Fc-fusion protein formulated in sorbitol upon frozen storage for extended periods of time at -30 degrees C. MATERIALS AND METHODS: We designed sub-ambient differential scanning calorimetry (DSC) experiments to capture the effects of long-term frozen storage. The physical stability of formulation samples was monitored by size exclusion high performance liquid chromatography (SE-HPLC). RESULTS: DSC analysis of non-frozen samples shows the expected glass transitions (Tg') at -45 degrees C for samples in sorbitol and at -32 degrees C in sucrose. In time course studies where sorbitol formulations were stored at -30 degrees C and analyzed by DSC without thawing, two endothermic transitions were observed: a melting endotherm at -20 degrees C dissipated over time, and a second endotherm at -8 degrees C was seen after approximately 2 weeks and persisted in all later time points. Protein aggregation was only seen in the samples formulated in sorbitol and stored at -30 degrees C, correlating aggregation with the aforementioned melts. CONCLUSIONS: The observed melts are characteristic of crystalline substances and suggest that the sorbitol crystallizes over time. During freezing, the excipient must remain in the same phase as the protein to ensure protein stability. By crystallizing, the sorbitol is phase-separated from the protein, which leads to protein aggregation.

Calorimetry, Differential Scanning↗
PubMed2006

Protein aggregate myopathies.

Protein aggregate myopathies (PAMs) based on the morphologic phenomenon of aggregation of proteins within muscle fibers may occur in children (selenoproteinopathies, actinopathies, and myosinopathies) or adults (certain myofibrillar myopathies and myosinopathies). They may be mutation related, which includes virtually all childhood forms but certain other forms as well, or sporadic, which are largely seen in adults. Their classification as myofibrillar or desmin-related myopathies, actinopathies, or myosinopathies is based on the identification of respective mutant proteins, most of them components of the sarcomeres. Recognition of PAM requires muscle biopsy and an extensive immunohistochemical and electron microscopic workup of the biopsied muscle tissue after which molecular analysis of morphologically ascertained proteins should ensue to permit recognition of individual entities and genetic counseling of patients and families. Because pathogenetic principles in PAMs are still incompletely known, causative therapy, at this time, is not available.

Animals↗