The Extracellular Chaperone Haptoglobin Prevents Serum Fatty Acid-promoted Amyloid Fibril Formation of β2-Microglobulin, Resistance to Lysosomal Degradation, and Cytotoxicity

Sultan, Abdullah; Raman, Bakthisaran; Rao, Ch. Mohan; Tangirala, Ramakrishna

doi:10.1074/jbc.m113.498337

Cited by 21 publications

(15 citation statements)

References 50 publications

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“…Similar results have been previously shown for chaperones [34][35][36], some non-chaperone proteins such as pyruvate kinase and seeds. Particles with all dimensions smaller than 30 nm were defined as oligomers while particles with any dimension over 30 nm were defined as fibrils catalase [37] and some small molecules [28].…”

Section: Discussionsupporting

confidence: 90%

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Pseudocatalytic Antiaggregation Activity of Antibodies: Immunoglobulins can Influence α-Synuclein Aggregation at Substoichiometric Concentrations

2015

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Protein aggregation is involved in a variety of diseases. Alteration of the aggregation pathway, either to produce less toxic structures or to increase aggregate clearance, is a promising therapeutic route. Both active and passive immunization has been used for this purpose. However, the mechanism of action of antibodies on protein aggregates is not completely clear especially given poor ability of antibodies to cross blood-brain barrier. Here, we have shown that antibodies can interfere with protein aggregation at substoichiometric concentrations (as low as 1:1000 antibody to protein ratio). This is an indication that antibodies interact with aggregation intermediates in chaperone-like manner altering the aggregation pathways at very low antibody levels. This observation supports earlier suggestions that antibodies can inhibit aggregation by interaction with low abundance aggregation intermediates.

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Section: Discussionsupporting

confidence: 90%

“…Particles with all dimensions smaller than 30 nm were defined as oligomers while particles with any dimension over 30 nm were defined as fibrils catalase [37] and some small molecules [28]. Both chaperone and non-chaperone proteins that inhibited protein aggregation were shown to bind to target proteins [34,35,37,36].…”

Section: Discussionmentioning

confidence: 99%

Pseudocatalytic Antiaggregation Activity of Antibodies: Immunoglobulins can Influence α-Synuclein Aggregation at Substoichiometric Concentrations

2015

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“…Previous studies have shown the effects of chaperones (39–41), metal ions (19, 32, 42), membranes (43), trifluoroethanol or SDS co-solvents (28, 29, 44), GAGs (18, 30, 45, 46), and other natural compounds (13, 17, 47) on the formation of amyloid fibrils in vitro . For some of these compounds, detailed kinetic analysis has revealed the effect of each reagent on the different kinetic steps in aggregation, including primary nucleation, elongation from fibril ends, and secondary processes such as fibril fragmentation and secondary nucleation (39–41, 43, 48). Such studies can provide important information on the role of biologically relevant and other compounds on amyloid formation, including how the different factors may act synergistically to alter the course of aggregation in an in vitro setting (17, 30).…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix components modulate different stages in β2-microglobulin amyloid formation

Benseny‐Cases

Karamanos

Hoop

et al. 2019

Journal of Biological Chemistry

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Amyloid deposition of WT human β 2 -microglobulin (WT-hβ 2 m) in the joints of long-term hemodialysis patients is the hallmark of dialysis-related amyloidosis. In vitro , WT-hβ 2 m does not form amyloid fibrils at physiological pH and temperature unless co-solvents or other reagents are added. Therefore, understanding how fibril formation is initiated and maintained in the joint space is important for elucidating WT-hβ 2 m aggregation and dialysis-related amyloidosis onset. Here, we investigated the roles of collagen I and the commonly administered anticoagulant, low-molecular-weight (LMW) heparin, in the initiation and subsequent aggregation phases of WT-hβ 2 m in physiologically relevant conditions. Using thioflavin T fluorescence to study the kinetics of amyloid formation, we analyzed how these two agents affect specific stages of WT-hβ 2 m assembly. Our results revealed that LMW-heparin strongly promotes WT-hβ 2 m fibrillogenesis during all stages of aggregation. However, collagen I affected WT-hβ 2 m amyloid formation in contrasting ways: decreasing the lag time of fibril formation in the presence of LMW-heparin and slowing the rate at higher concentrations. We found that in self-seeded reactions, interaction of collagen I with WT-hβ 2 m amyloid fibrils attenuates surface-mediated growth of WT-hβ 2 m fibrils, demonstrating a key role of secondary nucleation in WT-hβ 2 m amyloid formation. Interestingly, collagen I fibrils did not suppress surface-mediated assembly of WT-hβ 2 m monomers when cross-seeded with fibrils formed from the N-terminally truncated variant ΔN6-hβ 2 m. Together, these results provide detailed insights into how collagen I and LMW-heparin impact different stages in the aggregation of WT-hβ 2 m into amyloid, which lead to dramatic effects on the time course of assembly.

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“…Motomiya et al reported that b2M fragments having C-terminal unfolding, including a fragment lacking the first 6 amino acids (DN6b2M), 13 which has been recognized as an important amyloidogenic form, are essential for amyloidogenesis. 14 15 Naiki et al, 16,17 and other researchers 18…”

Section: Of B 2m and Amyloid Fibr Il Formationmentioning

confidence: 95%

“…Hereditary systemic amyloidosis due to the Asp76Asn‐β2M variant—a new type of Aβ2M with normal renal function—also suggests the importance of conformational change for β2M amyloidogenesis . Naiki et al, and other researchers identified numerous promoters (ie, type 1,2 collagen, glycosaminoglycan including heparin, proteoglycan, apolipoprotein E, lysophospholipid, free fatty acids, and pentraxins (serum amyloid P component and C‐reactive protein), and inhibitors (ie, α2 macroglobulin and haptoglobin)) of Aβ2M formation and elongation in in vitro studies.…”

Section: Pathogenesis Of Dra: Retention Of β2m and Amyloid Fibril Formentioning

confidence: 99%

Hemodialysis‐related amyloidosis: Is it still relevant?

Kaneko

Yamagata

2018

Seminars in Dialysis

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Accumulation of amyloid fibrils from β2-microglobulin (β2M) was first recognized as a characteristic osteoarticular complication in long-term hemodialysis (HD) patients and called "HD-related amyloidosis" (HRA). However, this syndrome can also be observed in end-stage renal diseases (ESRD) patients undergoing peritoneal dialysis, and even in patients with chronic renal failure before the initiation of dialytic therapy, suggesting that HD is not a direct cause but that accumulation of β2M or some β2M-associated molecules in the body is a common pathogenesis. Currently the term "dialysis-related amyloidosis" (DRA) is widely used for β2M-amyloid (Aβ2M) amyloidosis associated with ESRD, although DRA patients consist mostly of those undergoing long-term HD. Factors other than β2M accumulation also play a role in the formation/local deposition of Aβ2M and disruption of tissue architecture. Conformational changes of β2M by misfolding/unfolding, and promoting/inhibitory effects induced by other coexisting molecules, advanced glycation and oxidation, and direct cell toxicity have also been documented. Two technological improvements of HD have been the keys to prevent the development and progression of DRA: the efficient removal of β2M by using high-flux membranes, high-volume convection and adsorptive column/membrane, as well as the use of biocompatible membranes and dialysates (eg, ultrapure and acetate-free dialysates) have minimized both inflammation and β2M production. Epidemiologically, a decrease in the incidence of DRA has recently been reported; however, longer survival of HD patients may contribute to the development of more DRA, though with a delayed onset. In this article, we describe the pathogenesis of DRA, the strategies developed for its prevention and minimization, and the favorable epidemiological data achieved by these efforts.

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The Extracellular Chaperone Haptoglobin Prevents Serum Fatty Acid-promoted Amyloid Fibril Formation of β2-Microglobulin, Resistance to Lysosomal Degradation, and Cytotoxicity

Cited by 21 publications

References 50 publications

Pseudocatalytic Antiaggregation Activity of Antibodies: Immunoglobulins can Influence α-Synuclein Aggregation at Substoichiometric Concentrations

Pseudocatalytic Antiaggregation Activity of Antibodies: Immunoglobulins can Influence α-Synuclein Aggregation at Substoichiometric Concentrations

Extracellular matrix components modulate different stages in β2-microglobulin amyloid formation

Hemodialysis‐related amyloidosis: Is it still relevant?

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