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

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
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引用次数: 0

Abstract

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.

神经胶质过表达Tspo可延长果蝇的寿命并防止其缺乏 frataxin。
转运蛋白 TSPO 是一种进化保守的线粒体蛋白,在神经变性的各种情况下都会过度表达。弗里德里希共济失调症(Friedreich Ataxia,FA)是一种神经退行性疾病,是由于 FXN 基因中的 GAA 扩增导致 frataxin(一种参与铁硫簇生物合成的线粒体蛋白)表达减少所致。我们以前曾报道过,通过 CRISPR/Cas9 在果蝇 frataxin 基因 fh 的内含子中插入约 200 个 GAA,Tspo 在果蝇模型中过度表达。在这里,我们描述了一种带有 42 个 GAA 重复序列(称为 fh-GAAs)的新型 FA 果蝇模型。较小的扩增尺寸使得获得的成体表现出了FA疾病的特征,包括寿命短、运动缺陷和对氧化应激过敏。人类 FXN 的普遍表达可完全缓解寿命缩短的问题,这证实了两种 frataxins 具有相同的保守功能。我们观察到 Tspo 在这些 fh-GAAs 苍蝇的头部过表达,而在肠道中则减少。然后,我们进一步在神经胶质细胞中特异性地过表达了Tspo,并观察到存活率有所提高。最后,我们研究了Tspo过表达对健康苍蝇的影响。神经胶质细胞的特异性过表达延长了苍蝇的寿命,而神经元的过表达则产生了相反的效果。总之,这项研究强调了神经胶质 TSPO 对果蝇神经退行性疾病和健康的保护作用。
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来源期刊
Biochimie
Biochimie 生物-生化与分子生物学
CiteScore
7.20
自引率
2.60%
发文量
219
审稿时长
40 days
期刊介绍: Biochimie publishes original research articles, short communications, review articles, graphical reviews, mini-reviews, and hypotheses in the broad areas of biology, including biochemistry, enzymology, molecular and cell biology, metabolic regulation, genetics, immunology, microbiology, structural biology, genomics, proteomics, and molecular mechanisms of disease. Biochimie publishes exclusively in English. Articles are subject to peer review, and must satisfy the requirements of originality, high scientific integrity and general interest to a broad range of readers. Submissions that are judged to be of sound scientific and technical quality but do not fully satisfy the requirements for publication in Biochimie may benefit from a transfer service to a more suitable journal within the same subject area.
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