Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila

The translocator protein TSPO is an evolutionary conserved mitochondrial protein overexpressed in various contexts of neurodegeneration. Friedreich Ataxia (FA) is a neurodegenerative disease due to GAA expansions in the FXN gene leading to decreased expression of frataxin, a mitochondrial protein in...

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Published inBiochimie Vol. 224; pp. 71 - 79
Main Authors Jullian, Estelle, Russi, Maria, Turki, Ema, Bouvelot, Margaux, Tixier, Laura, Middendorp, Sandrine, Martin, Elodie, Monnier, Véronique
Format Journal Article
LanguageEnglish
Published France Elsevier B.V 01.09.2024
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Summary:The translocator protein TSPO is an evolutionary conserved mitochondrial protein overexpressed in various contexts of neurodegeneration. Friedreich Ataxia (FA) is a neurodegenerative disease due to GAA expansions in the FXN gene leading to decreased expression of frataxin, a mitochondrial protein involved in the biosynthesis of iron-sulfur clusters. We previously reported that Tspo was overexpressed in a Drosophila model of this disease generated by CRISPR/Cas9 insertion of approximately 200 GAA in the intron of fh, the fly frataxin gene. Here, we describe a new Drosophila model of FA with 42 GAA repeats, called fh-GAAs. The smaller expansion size allowed to obtain adults exhibiting hallmarks of the FA disease, including short lifespan, locomotory defects and hypersensitivity to oxidative stress. The reduced lifespan was fully rescued by ubiquitous expression of human FXN, confirming that both frataxins share conserved functions. We observed that Tspo was overexpressed in heads and decreased in intestines of these fh-GAAs flies. Then, we further overexpressed Tspo specifically in glial cells and observed improved survival. Finally, we investigated the effects of Tspo overexpression in healthy flies. Increased longevity was conferred by glial-specific overexpression, with opposite effects in neurons. Overall, this study highlights protective effects of glial TSPO in Drosophila both in a neurodegenerative and a healthy context. •A 42 GAA-based Drosophila model of Friedreich Ataxia exhibit hallmarks of the disease.•Overexpression of Tspo in glial cells improves survival of frataxin-deficient flies.•Glial but not neuron-specific overexpression of Tspo increases Drosophila lifespan.
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ISSN:0300-9084
1638-6183
1638-6183
DOI:10.1016/j.biochi.2024.05.003