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

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 investigati...

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Main Authors: Deianira Bellitto, Matteo Bozzo, Silvia Ravera, Nadia Bertola, Francesca Rosamilia, Jessica Milia, Paola Barboro, Gabriela Coronel Vargas, Donatella Di Lisa, Laura Pastorino, Francesca Lantieri, Patrizio Castagnola, Erika Iervasi, Marco Ponassi, Aldo Profumo, Kateryna Tkachenko, Camillo Rosano, Simona Candiani, Tiziana Bachetti
Format: Article
Language:English
Published: Elsevier 2025-04-01
Series:Redox Biology
Subjects:
Neurodegeneration
Proteomics
Transcriptomics
Leukodystrophy
Astrocytes
GFAP
Online Access:http://www.sciencedirect.com/science/article/pii/S2213231725000576
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Summary: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.
ISSN:2213-2317

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