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Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening

Department of Earth, Environment and Life Sciences (DISTAV), University of Genoa, 16132 Genoa, Italy
Institut für Klinische Anatomie und Zellanalytik, Universitaet Tuebingen, 72076 Tuebingen, Germany
Department of Clinical and Experimental Medicine, University of Florence, 50121 Florence, Italy
Department of Biology, University of Pisa, 56126 Pisa, Italy
Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 56122 Pisa, Italy
Laboratory of Genetics and Genomics of Rare Diseases, Unità Operativa Semplice Dipartimentale, Istituto Giannina Gaslini, 16147 Genoa, Italy
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Present address: Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy.
Genes 2020, 11(12), 1490;
Received: 13 November 2020 / Revised: 4 December 2020 / Accepted: 7 December 2020 / Published: 11 December 2020
(This article belongs to the Special Issue Zebrafish Animal Models)
Alexander disease (AxD) is a rare astrogliopathy caused by heterozygous mutations, either inherited or arising de novo, on the glial fibrillary acid protein (GFAP) gene (17q21). Mutations in the GFAP gene make the protein prone to forming aggregates which, together with heat-shock protein 27 (HSP27), αB-crystallin, ubiquitin, and proteasome, contribute to form Rosenthal fibers causing a toxic effect on the cell. Unfortunately, no pharmacological treatment is available yet, except for symptom reduction therapies, and patients undergo a progressive worsening of the disease. The aim of this study was the production of a zebrafish model for AxD, to have a system suitable for drug screening more complex than cell cultures. To this aim, embryos expressing the human GFAP gene carrying the most severe p.R239C under the control of the zebrafish gfap gene promoter underwent functional validation to assess several features already observed in in vitro and other in vivo models of AxD, such as the localization of mutant GFAP inclusions, the ultrastructural analysis of cells expressing mutant GFAP, the effects of treatments with ceftriaxone, and the heat shock response. Our results confirm that zebrafish is a suitable model both to study the molecular pathogenesis of GFAP mutations and to perform pharmacological screenings, likely useful for the search of therapies for AxD. View Full-Text
Keywords: Alexander disease; glial fibrillary acid protein; zebrafish; microinjection Alexander disease; glial fibrillary acid protein; zebrafish; microinjection
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MDPI and ACS Style

Candiani, S.; Carestiato, S.; Mack, A.F.; Bani, D.; Bozzo, M.; Obino, V.; Ori, M.; Rosamilia, F.; De Sarlo, M.; Pestarino, M.; Ceccherini, I.; Bachetti, T. Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening. Genes 2020, 11, 1490.

AMA Style

Candiani S, Carestiato S, Mack AF, Bani D, Bozzo M, Obino V, Ori M, Rosamilia F, De Sarlo M, Pestarino M, Ceccherini I, Bachetti T. Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening. Genes. 2020; 11(12):1490.

Chicago/Turabian Style

Candiani, Simona, Silvia Carestiato, Andreas F. Mack, Daniele Bani, Matteo Bozzo, Valentina Obino, Michela Ori, Francesca Rosamilia, Miriam De Sarlo, Mario Pestarino, Isabella Ceccherini, and Tiziana Bachetti. 2020. "Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening" Genes 11, no. 12: 1490.

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