Abstract
Availability of living organisms to mimic key step of amyloidogenesis of human protein has become an indispensable tool for our translation approach aiming at filling the deep gap existing between the biophysical and biochemical data obtained in vitro and the pathological features observed in patients. Human β2-microglobulin (β2-m) causes systemic amyloidosis in haemodialysed patients. The structure, misfolding propensity, kinetics of fibrillogenesis and cytotoxicity of this protein, in vitro, have been studied more extensively than for any other globular protein. However, no suitable animal model for β2-m amyloidosis has been so far reported. We have now established and characterized three new transgenic C. elegans strains expressing wild type human β2-m and two highly amyloidogenic isoforms: P32G variant and the truncated form ΔN6 lacking of the 6 N-terminal residues. The expression of human β2-m affects the larval growth of C. elegans and the severity of the damage correlates with the intrinsic propensity to self-aggregate that has been reported in previous in vitro studies. We have no evidence of the formation of amyloid deposits in the body-wall muscles of worms. However, we discovered a strict correlation between the pathological phenotype and the presence of oligomeric species recognized by the A11 antibody. The strains expressing human β2-m exhibit a locomotory defect quantified with the body bends assay. Here we show that tetracyclines can correct this abnormality confirming that these compounds are able to protect a living organism from the proteotoxicity of human β2-m.
| Original language | English |
|---|---|
| Article number | e52314 |
| Journal | PLoS One |
| Volume | 7 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 25 2012 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
C. elegans Expressing Human β2-Microglobulin : A Novel Model for Studying the Relationship between the Molecular Assembly and the Toxic Phenotype. / Diomede, Luisa; Soria, Cristina; Romeo, Margherita; Giorgetti, Sofia; Marchese, Loredana; Mangione, Patrizia Palma; Porcari, Riccardo; Zorzoli, Irene; Salmona, Mario; Bellotti, Vittorio; Stoppini, Monica.
In: PLoS One, Vol. 7, No. 12, e52314, 25.12.2012.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - C. elegans Expressing Human β2-Microglobulin
T2 - A Novel Model for Studying the Relationship between the Molecular Assembly and the Toxic Phenotype
AU - Diomede, Luisa
AU - Soria, Cristina
AU - Romeo, Margherita
AU - Giorgetti, Sofia
AU - Marchese, Loredana
AU - Mangione, Patrizia Palma
AU - Porcari, Riccardo
AU - Zorzoli, Irene
AU - Salmona, Mario
AU - Bellotti, Vittorio
AU - Stoppini, Monica
PY - 2012/12/25
Y1 - 2012/12/25
N2 - Availability of living organisms to mimic key step of amyloidogenesis of human protein has become an indispensable tool for our translation approach aiming at filling the deep gap existing between the biophysical and biochemical data obtained in vitro and the pathological features observed in patients. Human β2-microglobulin (β2-m) causes systemic amyloidosis in haemodialysed patients. The structure, misfolding propensity, kinetics of fibrillogenesis and cytotoxicity of this protein, in vitro, have been studied more extensively than for any other globular protein. However, no suitable animal model for β2-m amyloidosis has been so far reported. We have now established and characterized three new transgenic C. elegans strains expressing wild type human β2-m and two highly amyloidogenic isoforms: P32G variant and the truncated form ΔN6 lacking of the 6 N-terminal residues. The expression of human β2-m affects the larval growth of C. elegans and the severity of the damage correlates with the intrinsic propensity to self-aggregate that has been reported in previous in vitro studies. We have no evidence of the formation of amyloid deposits in the body-wall muscles of worms. However, we discovered a strict correlation between the pathological phenotype and the presence of oligomeric species recognized by the A11 antibody. The strains expressing human β2-m exhibit a locomotory defect quantified with the body bends assay. Here we show that tetracyclines can correct this abnormality confirming that these compounds are able to protect a living organism from the proteotoxicity of human β2-m.
AB - Availability of living organisms to mimic key step of amyloidogenesis of human protein has become an indispensable tool for our translation approach aiming at filling the deep gap existing between the biophysical and biochemical data obtained in vitro and the pathological features observed in patients. Human β2-microglobulin (β2-m) causes systemic amyloidosis in haemodialysed patients. The structure, misfolding propensity, kinetics of fibrillogenesis and cytotoxicity of this protein, in vitro, have been studied more extensively than for any other globular protein. However, no suitable animal model for β2-m amyloidosis has been so far reported. We have now established and characterized three new transgenic C. elegans strains expressing wild type human β2-m and two highly amyloidogenic isoforms: P32G variant and the truncated form ΔN6 lacking of the 6 N-terminal residues. The expression of human β2-m affects the larval growth of C. elegans and the severity of the damage correlates with the intrinsic propensity to self-aggregate that has been reported in previous in vitro studies. We have no evidence of the formation of amyloid deposits in the body-wall muscles of worms. However, we discovered a strict correlation between the pathological phenotype and the presence of oligomeric species recognized by the A11 antibody. The strains expressing human β2-m exhibit a locomotory defect quantified with the body bends assay. Here we show that tetracyclines can correct this abnormality confirming that these compounds are able to protect a living organism from the proteotoxicity of human β2-m.
UR - http://www.scopus.com/inward/record.url?scp=84871356165&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871356165&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0052314
DO - 10.1371/journal.pone.0052314
M3 - Article
C2 - 23284985
AN - SCOPUS:84871356165
VL - 7
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 12
M1 - e52314
ER -