High-molecular-mass proteins in haemodialysis-associated amyloidosis

Argilés, Àngel; Mourad, Georges; Axelrud-Cavadore, Claude; Watrin, Annette; Mion, C; Cavadore, Jean‐Claude

doi:10.1042/cs0760547

Cited by 40 publications

(20 citation statements)

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“…2A). This is consistent with the previous report of ␣2M identified in amyloid deposits from patients with DRA (22).…”

Section: Effect Of ␣2m On Seed-dependent Growth Of ␤2-m Amyloidsupporting

confidence: 83%

“…glycosaminoglycans, apolipoproteins, and glycoproteins (4), suggesting that these molecules affect the deposition of amyloid fibrils. ␣2M was found in amyloid deposits from patients with DRA (22). Moreover, the complex of ␣2M with ␤2-m was detected in serum obtained from the patients (23).…”

Section: Figure 5 Interaction Of Tetrameric and Dimeric ␣2m With ␤2-mentioning

confidence: 85%

“…Although ␣2M interacted with the amyloid fibrils ( Fig. 2A), this complex may be too huge to be removed from the extracellular space via receptor-mediated endocytosis and lysosomal degradation, leading to the co-deposition of ␣2M with amyloid fibrils in vivo (22).…”

Section: Figure 5 Interaction Of Tetrameric and Dimeric ␣2m With ␤2-mentioning

confidence: 99%

“…The trapping of proteases is accompanied by a conformational change of ␣2M, which exposes receptor binding domains and consequently undergoes endocytosis by binding to low density lipoprotein receptor-related protein (20,21). In patients with DRA, ␣2M is identified in the amyloid deposits (22) and forms a complex with ␤2-m in the blood (23). Serum concentrations of the ␣2M⅐␤2-m complex are correlated with the progression of DRA (23).…”

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confidence: 99%

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Inhibition of β2-Microglobulin Amyloid Fibril Formation by α2-Macroglobulin

Ozawa

Hara

Lee

et al. 2011

Journal of Biological Chemistry

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The relationship between various amyloidoses and chaperones is gathering attention. In patients with dialysis-related amyloidosis, ␣ 2 -macroglobulin (␣2M), an extracellular chaperone, forms a complex with ␤ 2 -microglobulin (␤2-m), a major component of amyloid fibrils, but the molecular mechanisms and biological implications of the complex formation remain unclear. Here, we found that ␣2M substoichiometrically inhibited the ␤2-m fibril formation at a neutral pH in the presence of SDS, a model for anionic lipids. Binding analysis showed that the binding affinity between ␣2M and ␤2-m in the presence of SDS was higher than that in the absence of SDS. Importantly, SDS dissociated tetrameric ␣2M into dimers with increased surface hydrophobicity. Western blot analysis revealed that both tetrameric and dimeric ␣2M interacted with SDS-denatured ␤2-m. At a physiologically relevant acidic pH and in the presence of heparin, ␣2M was also dissociated into dimers, and both tetrameric and dimeric ␣2M interacted with ␤2-m, resulting in the inhibition of fibril growth reaction. These results suggest that under conditions where native ␤2-m is denatured, tetrameric ␣2M is also converted to dimeric form with exposed hydrophobic surfaces to favor the hydrophobic interaction with denatured ␤2-m, thus dimeric ␣2M as well as tetrameric ␣2M may play an important role in controlling ␤2-m amyloid fibril formation.A number of proteins and peptides can misfold into ␤-sheetrich structures, called amyloid fibrils (1). The deposition of amyloid fibrils in intra-and extracellular spaces is responsible for more than 40 serious diseases, including Alzheimer and Parkinson diseases and dialysis-related amyloidosis (DRA) 2 (1). ␤ 2 -Microglobulin (␤2-m) is a major structural component of amyloid fibrils in DRA, a common and serious complication in long term hemodialysis patients (2). The formation of ␤2-m amyloid fibrils is thought to be induced by partial unfolding of ␤2-m (3, 4). Several groups have established conditions under which ␤2-m amyloid fibril formation occurs at a neutral pH (5-11). We found that ␤2-m amyloid fibrils are formed at a neutral pH in the presence of SDS (11). SDS below its critical micelle concentration unfolds the compact structure of ␤2-m to an amyloidogenic conformer and stabilizes the extended amyloid fibrils. SDS is an anionic detergent that mimics some characteristics of biological membranes and is considered to be a good model for anionic lipids. We recently reported that some lysophospholipids, especially lysophosphatidic acid as well as nonesterified fatty acids induce the extension of ␤2-m amyloid fibrils at a neutral pH by partially unfolding the compact structure of ␤2-m to an amyloidogenic conformer as well as by stabilizing the extended fibrils (6, 8). Although many groups have proposed the mechanisms by which ␤2-m amyloid fibrils are formed under physiological conditions, the biological machineries to inhibit the formation and deposition of ␤2-m amyloid fibrils are poorly understood (12).␣ 2 -Macroglobulin (...

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“…2A). This is consistent with the previous report of ␣2M identified in amyloid deposits from patients with DRA (22).…”

Section: Effect Of ␣2m On Seed-dependent Growth Of ␤2-m Amyloidsupporting

confidence: 83%

Section: Figure 5 Interaction Of Tetrameric and Dimeric ␣2m With ␤2-mentioning

confidence: 85%

Section: Figure 5 Interaction Of Tetrameric and Dimeric ␣2m With ␤2-mentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of β2-Microglobulin Amyloid Fibril Formation by α2-Macroglobulin

Ozawa

Hara

Lee

et al. 2011

Journal of Biological Chemistry

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show abstract

“…Amyloid P component [129], cystatin C [130], nexin II [131], α 1 -antichymotrypsin [132], antithrombin III and α 1 -antitrypsin [133], as well as α 2 -macroglobulin [134]are antiproteases, and they have been involved in a variety of amyloidoses including β 2 -microglobulin amyloidosis.…”

Section: β2-microglobulin-unrelated Factors: α2-macroglobulin and Antmentioning

confidence: 99%