Accumulation of αB-crystallin in brains of patients with Alexander's disease is not due to an abnormality of the 5′-flanking and coding sequence of the genomic DNA

Iwaki, Akiko; Iwaki, Toru; Goldman, James E.; Ogomori, Koji; Tateishi, Jun; Sakaki, Yoshiyuki

doi:10.1016/0304-3940(92)90689-5

Cited by 48 publications

(35 citation statements)

References 15 publications

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“…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%

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 Role Of Shsps In Neurodegenerative Diseasementioning

confidence: 99%

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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“…However, a related small heat shock protein HSP27, also known to associate with protein aggregates (38,39), was detected in accumulations formed by GFP-tagged CFTR C terminus but not in those containing HA-tagged CFTR C terminus or the N-terminal portion of huntingtin (Fig. 6C).…”

Section: Cftr-and Huntingtin-derived Peptides Form Separate Aggregatementioning

confidence: 99%

Aggregation of Misfolded Proteins Can Be a Selective Process Dependent upon Peptide Composition

Milewski

Mickle

Forrest

et al. 2002

Journal of Biological Chemistry

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Intracellular aggregation of misfolded proteins is observed in a number of human diseases, in particular, neurologic disorders in which expanded tracts of polyglutamine residues play a central role. A variety of other proteins are prone to aggregation when mutated, indicating that this process is a common pathologic mechanism for inherited disorders. However, little is known about the relationship between the sequence of aggregating peptides and the specificity of intracellular accumulation. Here we demonstrate that substitution of two residues eliminates aggregation of a 111-amino acid peptide derived from the C-terminal portion of the cystic fibrosis transmembrane conductance regulator (CFTR). We also show that fusion to a reporter protein considerably alters the subcellular distribution of aggregating peptide. When fused to green fluorescent protein, the peptide containing amino acids 1370 -1480 of CFTR accumulates in large perinuclear or nuclear aggregates. The same CFTR fragment devoid of green fluorescent protein localizes predominantly to discrete accumulations associated with mitochondria. Importantly, both types of accumulation are dependent on the presence of the same two amino acids within the CFTR sequence. Co-expression studies show that both CFTR-derived proteins can co-localize in large cytoplasmic/nuclear aggregates. However, neither CFTR construct accumulates in intracellular inclusions formed by N-terminal fragment of huntingtin. In addition to unique accumulation patterns, each aggregating peptide shows differences in association with chaperone proteins. Thus, our results indicate that the process of intracellular aggregation can be a selective process determined by the composition of the aggregating peptides.

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“…Expression of cxB-crystallin was found in many tissues, reaching levels of up to 2% in soleus muscle [15], and is increased in neuro-degenerative diseases [16,17], in brain tumors [18] or during oncogene expression [19]. In addition, expression of aB-crystallin can be induced by heat, osmotic and arsenite stress [20,21].…”

Section: Introductionmentioning

confidence: 99%

“…For the small heat shock proteins (sHSPs), which are ubiquitous and range in size from [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], cellular thermoresistance provided by their overexpression has been reported [6][7][8]. A striking sequence similarity exists between the C-terminal parts of proteins belonging to this group of HSPs and the uA-and aB-crystallins [5,9].…”

Section: Introductionmentioning

confidence: 99%

αA‐crystallin confers cellular thermoresistance

et al. 1994

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The bovine eye lens protein aA-crystallin has been overexpressed both by stable transfection of HeLa cells and by transient transfection of NIH 3T3 cells. In both experimental systems aA-crystallin overexpression results in an increased cellular thermoresistance as judged by different clonal survival assays. In contrast, similar overexpression of another stable lens protein,BB2-crystallin, does not confer thermoresistance. These results indicate that the structural relationship of aA-crystallin to the small heat shock proteins HSP25127 and to aB-crystallin is sufficient for the shared thermoprotective function of all of these molecules and strongly suggests that the chaperone-like properties that they have in common are responsible for the conferred cellular thermoresistance.

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Accumulation of αB-crystallin in brains of patients with Alexander's disease is not due to an abnormality of the 5′-flanking and coding sequence of the genomic DNA

Cited by 48 publications

References 15 publications

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

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

Aggregation of Misfolded Proteins Can Be a Selective Process Dependent upon Peptide Composition

αA‐crystallin confers cellular thermoresistance

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