Expression of αB-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/bf00296185

Cited by 205 publications

(87 citation statements)

References 27 publications

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“…UP in: neurons (in MNDs, NPD, AD, PD, CJD) [27][28][29][30][31][32] UP in: reactive glial cells, microglia, oligodendrocytes [11,13,16,17,33,34] þ þ [1] no [1] no [21] PD: þ þ [35] ALD: þ þ [36] cytoskeleton stabilization; maintaining the proper refractive index in the lens [37,38] (Continued. )…”

Section: Introductionmentioning

confidence: 99%

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Carra

Rusmini

Crippa

et al. 2013

Phil. Trans. R. Soc. B

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The family of the mammalian small heat-shock proteins consists of 10 members (sHSPs/HSPBs: HSPB1–HSPB10) that all share a highly conserved C-terminal alpha-crystallin domain, important for the modulation of both their structural and functional properties. HSPB proteins are biochemically classified as molecular chaperones and participate in protein quality control, preventing the aggregation of unfolded or misfolded proteins and/or assisting in their degradation. Thus, several members of the HSPB family have been suggested to be protective in a number of neurodegenerative and neuromuscular diseases that are characterized by protein misfolding. However, the pro-refolding, anti-aggregation or pro-degradative properties of the various members of the HSPB family differ largely, thereby influencing their efficacy and protective functions. Such diversity depends on several factors, including biochemical and physical properties of the unfolded/misfolded client, the expression levels and the subcellular localization of both the chaperone and the client proteins. Furthermore, although some HSPB members are inefficient at inhibiting protein aggregation, they can still exert neuroprotective effects by other, as yet unidentified, manners; e.g. by maintaining the proper cellular redox state or/and by preventing the activation of the apoptotic cascade. Here, we will focus our attention on how the differences in the activities of the HSPB proteins can influence neurodegenerative and neuromuscular disorders characterized by accumulation of aggregate-prone proteins. Understanding their mechanism of action may allow us to target a specific member in a specific cell type/disease for therapeutic purposes.

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Section: Introductionmentioning

confidence: 99%

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Carra

Rusmini

Crippa

et al. 2013

Phil. Trans. R. Soc. B

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“…Apart from maintaining lens transparency, its in vivo functions include interaction with intermediate filaments (29) and regulation of cytomorphological rearrangements during development (30). ␣B crystallin is hyperexpressed in neurological disorders such as Alzheimer's' disease, Creutzfeldt-Jacob disease, and Parkinson's disease (31)(32)(33).…”

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confidence: 99%

Domain Swapping in Human αA and αB Crystallins Affects Oligomerization and Enhances Chaperone-like Activity

Kumar¹,

Rao

2000

Journal of Biological Chemistry

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␣A and ␣B crystallins, members of the small heat shock protein family, prevent aggregation of proteins by their chaperone-like activity. These two proteins, although very homologous, particularly in the C-terminal region, which contains the highly conserved "␣-crystallin domain," show differences in their protective ability toward aggregation-prone target proteins. In order to investigate the differences between ␣A and ␣B crystallins, we engineered two chimeric proteins, ␣ANBC and ␣BNAC, by swapping the N-terminal domains of ␣A and ␣B crystallins. The chimeras were cloned and expressed in Escherichia coli. The purified recombinant wild-type and chimeric proteins were characterized by fluorescence and circular dichroism spectroscopy and gel permeation chromatography to study the changes in secondary, tertiary, and quaternary structure. Circular dichroism studies show structural changes in the chimeric proteins. ␣BNAC binds more 8-anilinonaphthalene-1-sulfonic acid than the ␣ANBC and the wild-type proteins, indicating increased accessible hydrophobic regions. The oligomeric state of ␣ANBC is comparable to wild-type ␣B homoaggregate. However, there is a large increase in the oligomer size of the ␣BNAC chimera. Interestingly, swapping domains results in complete loss of chaperone-like activity of ␣ANBC, whereas ␣BNAC shows severalfold increase in its protective ability. Our findings show the importance of the N-and C-terminal domains of ␣A and ␣B crystallins in subunit oligomerization and chaperone-like activity. Domain swapping results in an engineered protein with significantly enhanced chaperone-like activity.␣-Crystallin, a major lens protein having homology with small heat shock proteins (1-3), prevents aggregation of other proteins like a molecular chaperone (4). We had earlier shown that ␣-crystallin can prevent photo-aggregation of ␥-crystallin, which may have relevance in cataractogenesis (5). By using various non-thermal modes of aggregation, it was shown that chaperone-like activity of ␣-crystallin is temperature-dependent. A structural perturbation above 30°C enhances this activity severalfold (6, 7). In order to probe the molecular mechanism of the chaperone-like activity and its enhancement upon structural perturbation, we have been studying ␣-crystallin and its constituent subunits. Our recent study on the ␣A and ␣B homoaggregates showed that, despite high sequence homology, these proteins differ in their stability, chaperone-like activity, and the temperature dependence of this activity (8). This study also indicated different roles for the two proteins in the ␣-crystallin heteroaggregate in the eye lens and as separate proteins in non-lenticular tissues. Several investigators have introduced mutations in ␣A and ␣B crystallins to gain an insight into the structure-function relation (9 -12). Derham and Harding in their recent review (13) list about 30 sitedirected mutations from different laboratories. These mutations either result in some decrease or no change in the protective ability. It is interes...

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“…A few years ago, it was discovered that these subunits are also constitutively expressed in various non-lenticular tissues, suggesting that their function is more than merely structural (2)(3)(4)(5). In addition, increased expression of ␣B-crystallin has been observed in a variety of neurodegenerative disorders such as multiple sclerosis (6), Alexander's disease (7,8), and Alzheimer's disease (9,10). Although the physiological significance of this extralenticular expression is unknown, it certainly relates to the fact that ␣-crystallins belong to the family of small heat shock proteins (hsp) 1 (11,12).…”

mentioning

confidence: 99%

Immobilization of the C-terminal Extension of Bovine αA-Crystallin Reduces Chaperone-like Activity

Smulders

Carver

Lindner

et al. 1996

Journal of Biological Chemistry

123

110

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␣-Crystallins occur as multimeric complexes, which are able to suppress precipitation of unfolding proteins. Although the mechanism of this chaperone-like activity is unknown, the affinity of ␣-crystallin for aggregationprone proteins is probably based on hydrophobic interactions. ␣-Crystallins expose a considerable hydrophobic surface to solution, but nevertheless they are very stable and highly soluble. An explanation for this paradox may be that ␣-crystallin subunits have a polar and unstructured C-terminal extension that functions as a sort of solubilizer. In this paper we have described five ␣A-crystallins in which charged and hydrophobic residues were inserted in the C-terminal extension. Introduction of lysine, arginine, and aspartate does not substantially influence chaperone-like activity. In contrast, introduction of a hydrophobic tryptophan greatly diminishes functional activity. CD experiments indicate that this mutant has a normal secondary structure and fluorescence measurements show that the inserted tryptophan is located in a polar environment. However, NMR spectroscopy clearly demonstrates that the presence of the tryptophan residue dramatically reduces the flexibility of the C-terminal extension. Furthermore, the introduction of this tryptophan results in a considerably decreased thermostability of the protein. We conclude that changing the polarity of the C-terminal extension of ␣A-crystallin by insertion of a highly hydrophobic residue can seriously disturb structural and functional integrity.The composition of the vertebrate eye lens is dominated by a group of structural proteins known as crystallins. The largest of these, ␣-crystallin, is a dynamic multimeric complex composed of two types of homologous subunits, ␣A-and ␣B-crystallin (1). A few years ago, it was discovered that these subunits are also constitutively expressed in various non-lenticular tissues, suggesting that their function is more than merely structural (2-5). In addition, increased expression of ␣B-crystallin has been observed in a variety of neurodegenerative disorders such as multiple sclerosis (6), Alexander's disease (7,8), and Alzheimer's disease (9, 10). Although the physiological significance of this extralenticular expression is unknown, it certainly relates to the fact that ␣-crystallins belong to the family of small heat shock proteins (hsp) 1 (11, 12). Among the shared features of ␣-crystallins and other small hsp are the conferring of thermotolerance (13,14), interaction with actin (15, 16), phosphorylation (17, 18), and intracellular relocalization upon stress (19,20). Furthermore, in vitro experiments have shown that ␣A-and ␣B-crystallin as well as hsp25 can act as molecular chaperones by suppressing aggregation of denaturing proteins (21-23). Unfortunately, the mechanism of this functional activity is unclear because the three-dimensional structure of ␣-crystallin is unknown.Native ␣-crystallins occur as polydisperse particles with an average molecular mass of about 800 kDa. Understanding the multimeric arra...

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Expression of αB-crystallin in Alzheimer's disease

Cited by 205 publications

References 27 publications

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Domain Swapping in Human αA and αB Crystallins Affects Oligomerization and Enhances Chaperone-like Activity

Immobilization of the C-terminal Extension of Bovine αA-Crystallin Reduces Chaperone-like Activity

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