A multi-omics approach reveals impaired lipid metabolism and oxidative stress in a zebrafish model of Alexander disease

Alexander disease (AxD) is a rare leukodystrophy caused by heterozygous mutations in the GFAP gene. To date, several in vitro and in vivo models have been generated in an attempt to unravel the main mechanisms underlying this complex disease. However, none of these models is suitable for investigating the global dysregulation caused by AxD. To address this shortcoming, we have generated a stable transgenic zebrafish line (zAxD) carrying the human GFAP p.R239C mutation, which is associated with severe phenotypes of AxD type I patients. We then performed transcriptomics and proteomics analyses on the whole larvae of our zAxD model, confirming the involvement of several pathways such as the immune system response and inflammation, oxidative stress, extracellular matrix, lipoxidation and lipid metabolism, which were previously reported in more limited omic studies. Interestingly, new pathways emerged as well, including tyrosine and butanoate metabolic processes. Biochemical assays confirmed alterations in cell respiration and lipid metabolism as well as elevated oxidative stress. These findings confirm the reliability of the zAxD model to apply a whole-organism approach to investigate the molecular basis of the disease.

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Journal
Redox Biology
Published
2025-02-13
DOI
https://doi.org/10.1016/j.redox.2025.103544
Citations
1
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
0.81

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article

A multi-omics approach reveals impaired lipid metabolism and oxidative stress in a zebrafish model of Alexander disease

Marco Ponassi, Donatella Di Lisa, Paola Barboro, Jessica Milia et al.
1 citations
Redox Biology
RNA regulation and disease
0.81
article

A multi-omics approach reveals impaired lipid metabolism and oxidative stress in a zebrafish model of Alexander disease

Marco Ponassi, Donatella Di Lisa, Paola Barboro, Jessica Milia, Camillo Rosano, Nadia Bertola, Gabriela Coronel Vargas, Laura Pastorino, Francesca Rosamilia, Matteo Bozzo, Simona Candiani, Aldo Profumo, Tiziana Bachetti, Erika Iervasi, Silvia Ravera, Deianira Bellitto, Francesca Lantieri, Patrizio Castagnola, Kateryna Tkachenko
article en
1 citations

Abstract

Alexander disease (AxD) is a rare leukodystrophy caused by heterozygous mutations in the GFAP gene. To date, several in vitro and in vivo models have been generated in an attempt to unravel the main mechanisms underlying this complex disease. However, none of these models is suitable for investigating the global dysregulation caused by AxD. To address this shortcoming, we have generated a stable transgenic zebrafish line (zAxD) carrying the human GFAP p.R239C mutation, which is associated with severe phenotypes of AxD type I patients. We then performed transcriptomics and proteomics analyses on the whole larvae of our zAxD model, confirming the involvement of several pathways such as the immune system response and inflammation, oxidative stress, extracellular matrix, lipoxidation and lipid metabolism, which were previously reported in more limited omic studies. Interestingly, new pathways emerged as well, including tyrosine and butanoate metabolic processes. Biochemical assays confirmed alterations in cell respiration and lipid metabolism as well as elevated oxidative stress. These findings confirm the reliability of the zAxD model to apply a whole-organism approach to investigate the molecular basis of the disease.

Redox BiologyVol. 81
Center for Advanced Studies Research and Development in Sardinia (IT), Istituto Giannina Gaslini (IT), Ingegneria dei Sistemi (Italy) (IT), Ospedale Policlinico San Martino (IT), University of Genoa (IT)
EOSC-Life, Chonnam National University, Ministero della Salute, Università degli Studi di Genova
Zero hunger
Openalex Percentile: Top 31%
RNA regulation and disease
0.81
DOIOpen Access PDFOpenAlex
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