Glycosaminoglycans enhance the fibrillation propensity of the ß2-microglobulin cleavage variant--¿K58-ß2m

Dorthe B Corlin; Christina K Johnsen; Mogens H Nissen; Niels H H Heegaard

doi:10.1016/j.bbrc.2010.10.008

Glycosaminoglycans enhance the fibrillation propensity of the ß2-microglobulin cleavage variant--¿K58-ß2m

Dorthe B Corlin, Christina K Johnsen, Mogens H Nissen, Niels H H Heegaard

LUKKET: Institut for Immunologi og Mikrobiologi

6 Citationer (Scopus)

Abstract

Dialysis related amyloidosis (DRA) is a serious complication to long-term hemodialysis treatment which causes clinical symptoms such as carpal tunnel syndrome and destructive arthropathies. The disease is characterized by the assembly and deposition of β₂-microglobulin (β₂m) predominantly in the musculoskeletal system, but the initiating events leading to β₂m amyloidogenesis and the molecular mechanisms underlying amyloid fibril formation are still unclear. Glycosaminoglycans (GAGs) and metal ions have been shown to be related to the onset of protein aggregation and to promote de novo fiber formation. In this study, we show that fibrillogenesis of a cleavage variant of β₂m, ΔK58-β₂m, which can be found in the circulation of hemodialysis patients and is able to fibrillate at near-physiological pH in vitro, is affected by the presence of copper ions and heparan sulfate. It is found that the fibrils generated when heparan sulfate is present have increased length and diameter, and possess enhanced stability and seeding properties. However, when copper ions are present the fibrils are short, thin and less stable, and form at a slower rate. We suggest that heparan sulfate stabilizes the cleaved monomers in the early aggregates, hereby promoting the assembly of these into fibrils, whereas the copper ions appear to have a destabilizing effect on the monomers. This keeps them in a structure forming amorphous aggregates for a longer period of time, leading to the formation of spherical bodies followed by the assembly of fibrils. Hence, the in vivo formation of amyloid fibrils in DRA could be initiated by the generation of ΔK58-β₂m which spontaneously aggregate and form fibrils. The fibrillogenesis is enhanced by the involvement of GAGs and/or metal ions, and results in amyloid-like fibrils able to promote the de novo formation of β₂m amyloid by scaffold mechanism.

Originalsprog	Engelsk
Tidsskrift	Biochemical and Biophysical Research Communications
Vol/bind	402
Udgave nummer	2
Sider (fra-til)	247-51
Antal sider	5
ISSN	0006-291X
DOI	https://doi.org/10.1016/j.bbrc.2010.10.008
Status	Udgivet - 12 nov. 2010

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10.1016/j.bbrc.2010.10.008

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title = "Glycosaminoglycans enhance the fibrillation propensity of the {\ss}2-microglobulin cleavage variant--¿K58-{\ss}2m",

abstract = "Dialysis related amyloidosis (DRA) is a serious complication to long-term hemodialysis treatment which causes clinical symptoms such as carpal tunnel syndrome and destructive arthropathies. The disease is characterized by the assembly and deposition of β2-microglobulin (β2m) predominantly in the musculoskeletal system, but the initiating events leading to β2m amyloidogenesis and the molecular mechanisms underlying amyloid fibril formation are still unclear. Glycosaminoglycans (GAGs) and metal ions have been shown to be related to the onset of protein aggregation and to promote de novo fiber formation. In this study, we show that fibrillogenesis of a cleavage variant of β2m, ΔK58-β2m, which can be found in the circulation of hemodialysis patients and is able to fibrillate at near-physiological pH in vitro, is affected by the presence of copper ions and heparan sulfate. It is found that the fibrils generated when heparan sulfate is present have increased length and diameter, and possess enhanced stability and seeding properties. However, when copper ions are present the fibrils are short, thin and less stable, and form at a slower rate. We suggest that heparan sulfate stabilizes the cleaved monomers in the early aggregates, hereby promoting the assembly of these into fibrils, whereas the copper ions appear to have a destabilizing effect on the monomers. This keeps them in a structure forming amorphous aggregates for a longer period of time, leading to the formation of spherical bodies followed by the assembly of fibrils. Hence, the in vivo formation of amyloid fibrils in DRA could be initiated by the generation of ΔK58-β2m which spontaneously aggregate and form fibrils. The fibrillogenesis is enhanced by the involvement of GAGs and/or metal ions, and results in amyloid-like fibrils able to promote the de novo formation of β2m amyloid by scaffold mechanism.",

keywords = "Amyloid, Amyloidosis, Copper, Glycosaminoglycans, Heparitin Sulfate, Humans, Renal Dialysis, beta 2-Microglobulin",

author = "Corlin, {Dorthe B} and Johnsen, {Christina K} and Nissen, {Mogens H} and Heegaard, {Niels H H}",

year = "2010",

month = nov,

day = "12",

doi = "10.1016/j.bbrc.2010.10.008",

language = "English",

volume = "402",

pages = "247--51",

journal = "Biochemical and Biophysical Research Communications",

issn = "0006-291X",

publisher = "Elsevier",

number = "2",

}

TY - JOUR

T1 - Glycosaminoglycans enhance the fibrillation propensity of the ß2-microglobulin cleavage variant--¿K58-ß2m

AU - Corlin, Dorthe B

AU - Johnsen, Christina K

AU - Nissen, Mogens H

AU - Heegaard, Niels H H

PY - 2010/11/12

Y1 - 2010/11/12

N2 - Dialysis related amyloidosis (DRA) is a serious complication to long-term hemodialysis treatment which causes clinical symptoms such as carpal tunnel syndrome and destructive arthropathies. The disease is characterized by the assembly and deposition of β2-microglobulin (β2m) predominantly in the musculoskeletal system, but the initiating events leading to β2m amyloidogenesis and the molecular mechanisms underlying amyloid fibril formation are still unclear. Glycosaminoglycans (GAGs) and metal ions have been shown to be related to the onset of protein aggregation and to promote de novo fiber formation. In this study, we show that fibrillogenesis of a cleavage variant of β2m, ΔK58-β2m, which can be found in the circulation of hemodialysis patients and is able to fibrillate at near-physiological pH in vitro, is affected by the presence of copper ions and heparan sulfate. It is found that the fibrils generated when heparan sulfate is present have increased length and diameter, and possess enhanced stability and seeding properties. However, when copper ions are present the fibrils are short, thin and less stable, and form at a slower rate. We suggest that heparan sulfate stabilizes the cleaved monomers in the early aggregates, hereby promoting the assembly of these into fibrils, whereas the copper ions appear to have a destabilizing effect on the monomers. This keeps them in a structure forming amorphous aggregates for a longer period of time, leading to the formation of spherical bodies followed by the assembly of fibrils. Hence, the in vivo formation of amyloid fibrils in DRA could be initiated by the generation of ΔK58-β2m which spontaneously aggregate and form fibrils. The fibrillogenesis is enhanced by the involvement of GAGs and/or metal ions, and results in amyloid-like fibrils able to promote the de novo formation of β2m amyloid by scaffold mechanism.

AB - Dialysis related amyloidosis (DRA) is a serious complication to long-term hemodialysis treatment which causes clinical symptoms such as carpal tunnel syndrome and destructive arthropathies. The disease is characterized by the assembly and deposition of β2-microglobulin (β2m) predominantly in the musculoskeletal system, but the initiating events leading to β2m amyloidogenesis and the molecular mechanisms underlying amyloid fibril formation are still unclear. Glycosaminoglycans (GAGs) and metal ions have been shown to be related to the onset of protein aggregation and to promote de novo fiber formation. In this study, we show that fibrillogenesis of a cleavage variant of β2m, ΔK58-β2m, which can be found in the circulation of hemodialysis patients and is able to fibrillate at near-physiological pH in vitro, is affected by the presence of copper ions and heparan sulfate. It is found that the fibrils generated when heparan sulfate is present have increased length and diameter, and possess enhanced stability and seeding properties. However, when copper ions are present the fibrils are short, thin and less stable, and form at a slower rate. We suggest that heparan sulfate stabilizes the cleaved monomers in the early aggregates, hereby promoting the assembly of these into fibrils, whereas the copper ions appear to have a destabilizing effect on the monomers. This keeps them in a structure forming amorphous aggregates for a longer period of time, leading to the formation of spherical bodies followed by the assembly of fibrils. Hence, the in vivo formation of amyloid fibrils in DRA could be initiated by the generation of ΔK58-β2m which spontaneously aggregate and form fibrils. The fibrillogenesis is enhanced by the involvement of GAGs and/or metal ions, and results in amyloid-like fibrils able to promote the de novo formation of β2m amyloid by scaffold mechanism.

KW - Amyloid

KW - Amyloidosis

KW - Copper

KW - Glycosaminoglycans

KW - Heparitin Sulfate

KW - Humans

KW - Renal Dialysis

KW - beta 2-Microglobulin

U2 - 10.1016/j.bbrc.2010.10.008

DO - 10.1016/j.bbrc.2010.10.008

M3 - Journal article

C2 - 20939999

SN - 0006-291X

VL - 402

SP - 247

EP - 251

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

IS - 2

ER -

Glycosaminoglycans enhance the fibrillation propensity of the ß2-microglobulin cleavage variant--¿K58-ß2m

Abstract

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