The Molecular Chaperone αB-crystallin Enhances Amyloid β Neurotoxicity

Stege, G. J. J.; Renkawek, K; Overkamp, Perry; Verschuure, Pauline; Rijk, Anke F. van; Reijnen-Aalbers, A.; Boelens, Wilbert C.; Bosman, G.J.C.G.M.; Jong, Wilfried W. de

doi:10.1006/bbrc.1999.1167

Cited by 153 publications

(136 citation statements)

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“…Moreover, proteasome inhibition, which is present in s-IBM muscle fibers and is experimentally produced by AβPP overexpression in CHMFs [4], might additionally contribute to the αBC increase in s-IBM. Based on our data, and evidence of others in neuronal tissue [28], we propose that in s-IBM fibers αBC binding to Aβ oligomers with the "intent" to chaperone actually may be detrimental by preventing Aβ oligomers from assembling into the putatively non-toxic aggregates. Another possibly detrimental effect is that αBC bound to AβPP/Aβ might help induce or maintain the inflammatory reaction in s-IBM muscle [18].…”

Section: Discussionsupporting

confidence: 69%

“…In Alzheimer brain, αBC binds to AβPP [26], and αBC mRNA is increased (referenced in [26]). In vitro, αBC prevents Aβ fibril growth and spontaneous fibril formation, binds Aβ, and prevents its aggregation [27][28][29]. However, when applied extracellularly to cultured rat neurons, concomitantly with Aβ, αBC increases Aβ cytotoxicity [28], possibly due to αBC's influence in maintaining Aβ in its soluble oligomeric, highly cytotoxic form [28].…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, αBC prevents Aβ fibril growth and spontaneous fibril formation, binds Aβ, and prevents its aggregation [27][28][29]. However, when applied extracellularly to cultured rat neurons, concomitantly with Aβ, αBC increases Aβ cytotoxicity [28], possibly due to αBC's influence in maintaining Aβ in its soluble oligomeric, highly cytotoxic form [28]. Several studies have demonstrated that Aβ and other amyloidogenic proteins exert their cytotoxicity when in the form of oligomeric intermediates or "pre-amyloid" protofibrils, and not while in the form of insoluble amyloid fibrils or aggregates [12][13][14][15][16].…”

Section: Discussionmentioning

confidence: 99%

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AβPP-overexpression and proteasome inhibition increase αB-crystallin in cultured human muscle: Relevance to inclusion-body myositis

Wójcik

Engel

McFerrin

et al. 2006

Neuromuscular Disorders

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Amyloid-β precursor protein (AβPP) and its fragment amyloid-β (Aβ) are increased in s-IBM muscle fibers and appear to play an important role in the pathogenic cascade. αB-crystallin (αBC) was shown immunohistochemically to be accumulated in s-IBM muscle fibers, but the stressor(s) influencing αBC accumulation was not identified. We now demonstrate, using our experimental IBM model based on genetic overexpression of AβPP into normal culture human muscle fibers, that: 1) AβPP overexpression increased αBC 3.7-fold (p= 0.025); 2) additional inhibition of proteasome with epoxomicin increased αBC 7-fold (p=0.002); and 3) αBC physically associated with AβPP and Aβ oligomers. We also show that in biopsied s-IBM muscle fibers, αBC was similarly increased 3-fold (p=0.025) and physically associated with AβPP and Aβ oligomers. We propose that increased AβPP is a stressor increasing αBC expression in s-IBM muscle fibers. Determining the consequences of αBC association with Aβ oligomers could have clinical therapeutic relevance.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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AβPP-overexpression and proteasome inhibition increase αB-crystallin in cultured human muscle: Relevance to inclusion-body myositis

Wójcik

Engel

McFerrin

et al. 2006

Neuromuscular Disorders

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“…Thus, under fibril-forming conditions it will be ascertained whether clusterin and sHsps over-expression is deleterious to cell viability due to their potentiation of neurotoxicity via stabilization of intermediately-folded protofibril species, as has been implied from in vitro and cell culture studies [26,27]. The role of individual chaperones, and their possible synergistic interactions, in the modulation of fibril formation will also become much clearer.…”

Section: Unanswered Questions and Directions For Shsp And Clusterin Rmentioning

confidence: 99%

“…In vitro, B-crystallin and clusterin have both been found to inhibit amyloid fibril formation, e.g. by the amyloid -peptide (A), the putative causative agent in Alzheimer's disease [26][27][28]. However, in cell culture experiments, A-crystallin enhanced A  neurotoxicity, possibly by stabilizing the small soluble protofibril species (Fig.…”

Section: Parallels Between the Structure And Mechanism Of Chaperone Amentioning

confidence: 99%

Small Heat‐shock Proteins and Clusterin: Intra‐ and Extracellular Molecular Chaperones with a Common Mechanism of Action and Function?

et al. 2003

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Small heat-shock proteins (sHsps) and clusterin are molecular chaperones that share many functional similarities despite their lack of significant sequence similarity. These functional similarities, and some differences, are discussed. sHsps are ubiquitous intracellular proteins whereas clusterin is generally found extracellularly. Both chaperones potently prevent the amorphous aggregation and precipitation of target proteins under stress conditions such as elevated temperature, reduction and oxidation. In doing so, they act on the slow off-folding protein pathway. The conformational dynamism and aggregated state of both proteins may be crucial for their chaperone function. Subunit exchange is likely to be important in regulating chaperone action; the dissociated form of the protein is probably the chaperone-active species rather than the aggregated state. They both exert their chaperone action without the need for hydrolysis of ATP and have little ability to refold target proteins. Increased expression of sHsp and clusterin accompanies a range of diseases, e.g. Alzheimer's, Creutzfeldt-Jakob and Parkinson's diseases, that arise from protein misfolding and deposition of highly structured protein aggregates known as amyloid fibrils. The interaction of sHsps and clusterin with fibril-forming species is discussed along with their ability to prevent fibril formation, probably via utilization of their chaperone ability. Disciplines Life Sciences | Physical Sciences and Mathematics | Social and Behavioral Sciences Publication DetailsThis article was originally published as Carver, JA, Rekas, A, Thorn, DC and Wilson, MR, Small heat-shock proteins and clusterin: intra-and extracellular molecular chaperones with a common mechanism of action and function, IUBMB Life, 55, 2003, 661-668 AbstractSmall heat-shock proteins (sHsps) and clusterin are molecular chaperones that share many functional similarities despite their lack of significant sequence similarity. These functional similarities, and some differences, are discussed. sHsps are ubiquitous intracellular proteins whereas clusterin is generally found extracellularly. Both chaperones potently prevent the amorphous aggregation and precipitation of target proteins under stress conditions such as elevated temperature, reduction and oxidation. In doing so, they act on the slow off-folding protein pathway. The conformational dynamism and aggregated state of both proteins may be crucial for their chaperone function. Subunit exchange is likely to be important in regulating chaperone action; the dissociated form of the protein is probably the chaperone-active species rather than the aggregated state. They both exert their chaperone action without the need for hydrolysis of ATP and have little ability to refold target proteins. Increased expression of sHsp and clusterin accompanies a range of diseases, e.g. Alzheimer's, Creutzfeldt-Jakob and Parkinson's diseases, that arise from protein misfolding and deposition of highly structured protein aggregates known as amyloid f...

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Proteomic analysis of the brain in Alzheimer’s disease: Molecular phenotype of a complex disease process

et al. 2001

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for about 50% of all dementias, yet its pathogenic mechanisms remain poorly understood. In order to provide a more complete picture of pathogenesis in AD, we analysed six human brain regions for alterations in their proteomes. Quantitative proteome analysis was used to compare signals corresponding to individual proteins between post mortem brain tissues from persons with AD, and those from age-matched nondemented control (NC) tissues. In severely injured brain regions, 76 proteins were differentially expressed in AD hippocampus compared with NC, 62 proteins were differentially expressed in temporal cortex, and 39 proteins were differentially expressed in entorhinal cortex. Significant differences were also present in relatively spared regions. Thus, 34 proteins were differentially expressed in AD cerebellum compared with NC, 125 proteins were differentially expressed in cingulate gyrus, and 75 proteins were differentially expressed in sensorimotor cortex. The identity of 37 of these proteins was determined, and the possible relevance of changes in key pathogenic pathways analysed. These studies provide a unique snapshot illustrating the complexity of interrelated disease mechanisms at work in a complex, multifactorial disease, and show that comparative proteome analysis is a method with the power to develop important new insights into pathogenic mechanisms in the dementias.

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The Molecular Chaperone αB-crystallin Enhances Amyloid β Neurotoxicity

Cited by 153 publications

References 29 publications

AβPP-overexpression and proteasome inhibition increase αB-crystallin in cultured human muscle: Relevance to inclusion-body myositis

AβPP-overexpression and proteasome inhibition increase αB-crystallin in cultured human muscle: Relevance to inclusion-body myositis

Small Heat‐shock Proteins and Clusterin: Intra‐ and Extracellular Molecular Chaperones with a Common Mechanism of Action and Function?

Proteomic analysis of the brain in Alzheimer’s disease: Molecular phenotype of a complex disease process

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