C. elegans expressing D76N β2-microglobulin: a model for in vivo screening of drug candidates targeting amyloidosis

The availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of β 2 -microglobulin (D76N β 2 -m) is associated with a...

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Veröffentlicht in:Scientific reports 2019-12, Vol.9 (1), p.1-10, Article 19960
Hauptverfasser: Faravelli, Giulia, Raimondi, Sara, Marchese, Loredana, Partridge, Frederick A., Soria, Cristina, Mangione, P. Patrizia, Canetti, Diana, Perni, Michele, Aprile, Francesco A., Zorzoli, Irene, Di Schiavi, Elia, Lomas, David A., Bellotti, Vittorio, Sattelle, David B., Giorgetti, Sofia
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container_title Scientific reports
container_volume 9
creator Faravelli, Giulia
Raimondi, Sara
Marchese, Loredana
Partridge, Frederick A.
Soria, Cristina
Mangione, P. Patrizia
Canetti, Diana
Perni, Michele
Aprile, Francesco A.
Zorzoli, Irene
Di Schiavi, Elia
Lomas, David A.
Bellotti, Vittorio
Sattelle, David B.
Giorgetti, Sofia
description The availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of β 2 -microglobulin (D76N β 2 -m) is associated with a fatal familial form of systemic amyloidosis. Hitherto, no animal model has been available for studying in vivo the pathogenicity of this protein. We have established a transgenic C. elegans line, expressing the human D76N β 2 -m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N β 2 -m expressing worms. We also demonstrated the specificity of the β 2 -m variant in determining the pathological phenotype by rescuing the wild type phenotype when β 2 -m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. In future, this C. elegans model, in conjunction with the INVAPP/Paragon system, offers the prospect of high-throughput chemical screening in the search for new drug candidates.
doi_str_mv 10.1038/s41598-019-56498-5
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We have established a transgenic C. elegans line, expressing the human D76N β 2 -m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N β 2 -m expressing worms. We also demonstrated the specificity of the β 2 -m variant in determining the pathological phenotype by rescuing the wild type phenotype when β 2 -m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. 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subjects 38/77
38/89
45/22
45/23
45/29
45/44
631/1647
631/45
64/11
82
82/1
82/16
82/29
Amyloidogenesis
Amyloidosis
Animal models
Doxycycline
Drug development
Genotype & phenotype
Humanities and Social Sciences
Invertebrates
multidisciplinary
Pathogenicity
Pathogens
Phenotypes
Phenotyping
RNA-mediated interference
Science
Science (multidisciplinary)
Worms
β2 Microglobulin
title C. elegans expressing D76N β2-microglobulin: a model for in vivo screening of drug candidates targeting amyloidosis
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