Expression of ?B-crystallin in Alzheimer's disease

Renkawek, K; Voorter, Christina E.M.; Bosman, G.J.C.G.M.; Workum, F. P. A. van; Jong, Wilfried W. de

doi:10.1007/s004010050070

Cited by 50 publications

(64 citation statements)

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“…2 Most studies that have tested the in vitro chaperone action of sHsps have involved addition of the chaperone prior to aggregation commencing. Thus, the design of such studies does not address the effect(s) sHsps have on the latter stages of aggregation, which is as important to consider since, in vivo, levels of sHsps in the cell increase after aggregation has commenced as a result of the activation of the stress response [104,105]. Apart from interacting with monomeric species, sHsps also bind to species formed further along the aggregation pathway, including mature amyloid fibrils [106][107][108][109].…”

Section: The Chaperone Mechanism Of Shspsmentioning

confidence: 99%

“…In patients with familial AD, overproduction of A leads to early onset AD [182][183][184][185]. The level of Bc expression in brains of patients suffering AD is markedly increased compared to that in the normal human brain [105,186] presumably due to the cellular stress caused by disease. We and others have shown that aggregation of A and its associated cellular toxicity is prevented by Bc [187] or its isolated ACD [18] and thus sHsp overexpression in the context of AD may be as a protective mechanism.…”

Section: The Role Of Shsps In Neurodegenerative Diseasementioning

confidence: 99%

“…The precise role of Bc in the development and progression of this disease is still unknown, despite the findings that the disease is characterised by 'ballooned' neurons [195] which express Bc [105]. Both PD and Huntington's disease are intracellular protein aggregation diseases, like CJD.…”

Section: The Role Of Shsps In Neurodegenerative Diseasementioning

confidence: 99%

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Small heat-shock proteins: important players in regulating cellular proteostasis

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

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Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein aggregation under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) thereby avoiding the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. Significant progress has been made of late in understanding the structure and chaperone mechanism of sHsps. In this review, we discuss some of these advances, with a focus on mammalian sHsp hetero-oligomerisation, the mechanism by which sHsps act as molecular chaperones to prevent both amorphous and fibrillar protein aggregation, and the role of posttranslational modifications in sHsp chaperone function, particularly in the context of disease. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abstract (word count = 159)Small heat-shock proteins (sHsps) are a diverse family of intracellular molecular chaperone proteins that play a critical role in preventing protein unfolding, misfolding and aggregation, particularly under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) and thereby avoid the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. There has been much research into the structure and mechanism of chaperone action of sHsps over approximately the past 30 years, and significant progress has been made of late, however, there are still many unanswered questions relating to these aspects of sHsps. In this review, we outline some of the recent advances in understanding the structure and function of mammalian sHsps, particularly in the context of their many and varied roles in disease.

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Section: The Chaperone Mechanism Of Shspsmentioning

confidence: 99%

Section: The Role Of Shsps In Neurodegenerative Diseasementioning

confidence: 99%

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Small heat-shock proteins: important players in regulating cellular proteostasis

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

View full text Add to dashboard Cite

show abstract

“…For example, induction of sHsps has been reported in Alexander's disease [60], Creutzfeldt-Jakob disease [61], Alzheimer's disease, [62,63] and other neurological conditions [64][65][66][67][68][69]. Moreover, sHsps have been found to co-localize with the protein aggregates associated with a number of these protein misfolding diseases and/or are found at significant levels in neurons that surround the deposits (see below for details).…”

Section: Shsps and Diseasementioning

confidence: 99%

“…It also implies an important role for sHsps in amyloid diseases, indicating that they are the first line of defence for the cell in its attempt to mitigate amyloid fibril formation by the particular disease-associated protein. In particular, their localization to activated glia cells such as astrocytes [63,70] implies an important role for sHsps in these cells in neurodegenerative diseases. Despite the correlation between sHsp expression and co-localization with amyloid fibril deposits in various protein conformational diseases, the precise role of sHsps in interacting with the aggregating target protein and the subsequent effect on its toxicity remains controversial and may differ for various target proteins.…”

Section: Shsps and Diseasementioning

confidence: 99%

Crystallin proteins and amyloid fibrils

Ecroyd

Carver

2008

Cell. Mol. Life Sci.

220

234

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Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, alpha-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of alpha B-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials. Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, α-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of αB-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials.

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Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma

Liu

Garcia

et al. 2016

Glia

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Retinoic acid (RA), a metabolite of vitamin A, is required for the regulation of growth and development. Aberrant expression of molecules involved in RA signaling has been reported in various cancer types including glioblastoma multiforme (GBM). Cellular retinoic acid-binding protein 2 (CRABP2) has previously been shown to play a key role in the transport of RA to retinoic acid receptors (RARs) to activate their transcription regulatory activity. Here, we demonstrate that CRABP2 is predominantly located in the cytoplasm of GBM tumors. Cytoplasmic, but not nuclear, CRABP2 levels in GBM tumors are associated with poor patient survival. Treatment of malignant glioma cell lines with RA results in a dose-dependent increase in accumulation of CRABP2 in the cytoplasm. CRABP2 knockdown reduces proliferation rates of malignant glioma cells, and enhances RA-induced RAR activation. Levels of CRYAB, a small heat shock protein with anti-apoptotic activity, and GFAP, an astrocyte-specific intermediate filament protein, are greatly reduced in CRABP2-depleted cells. Restoration of CRYAB expression partially but significantly reversed the effect of CRABP2 depletion on RAR activation. Our combined in vivo and in vitro data indicate that: (i) CRABP2 is an important determinant of clinical outcome in GBM patients, and (ii) the mechanism of action of CRABP2 in GBM involves sequestration of RA in the cytoplasm and activation of an anti-apoptotic pathway, thereby enhancing proliferation and preventing RA-mediated cell death and differentiation. We propose that reducing CRABP2 levels may enhance the therapeutic index of RA in GBM patients.

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Expression of ?B-crystallin in Alzheimer's disease

Cited by 50 publications

References 0 publications

Small heat-shock proteins: important players in regulating cellular proteostasis

Small heat-shock proteins: important players in regulating cellular proteostasis

Crystallin proteins and amyloid fibrils

Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma

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