Investigating retrotransposon-derived eccDNA as a source of innate immune activation in tauopathy

IF 13 1区 医学 Q1 CLINICAL NEUROLOGY
Morgan Elizabeth Lambert, Paulino Ramirez, Wenyan Sun, Bess Frost
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Abstract

Background

Retrotransposon-derived extrachromosomal circular DNA (eccDNA) was extracted and sequenced from brains with Alzheimer’s disease, progressive supranuclear palsy, or healthy controls. Retrotransposon-derived DNA was visualized outside of the nucleus in these phenotypes with phospho-STING. Drosophila were used as a model to study extranuclear retrotransposon DNA.

Method

DNA was extracted from post-mortem human patients with AD (n = 6), PSP (FTD) (n = 6), or no pathology (n = 6). The DNA was treated with exonucleases to degrade linear DNA and the circular DNA was isolated. Post-mortem cryosections of AD, PSP, or healthy control brains were used for fluorescent in-situ hybridization (FISH) of retrotransposon sequences. Co-immunofluorescence of phospho-STING was performed on FISH tissue. Drosophila brains were also used for FISH of retrotransposons. Digital qPCR was used to measure copy number of retrotransposons in human and fly tissue.

Result

Preliminary data suggests an increase in phospho-STING in AD and PSP brains compared to controls. Preliminary data also suggests an enrichment of retrotransposon DNA in circular DNA sequencing in tau pathology compared to controls.

Conclusion

Retrotransposon-derived eccDNA may be an activator of the cGAS-STING pathway in AD and PSP.

研究逆转录转座子衍生的eccDNA作为牛头病先天免疫激活的来源
从阿尔茨海默病、进行性核上性麻痹或健康对照的大脑中提取转座子衍生的染色体外环状DNA (eccDNA)并对其进行测序。在这些表型中,用phospho - STING在细胞核外显示逆转录转座子衍生的DNA。以果蝇为模型研究核外反转录转座子DNA。方法从死后AD (n = 6)、PSP (FTD) (n = 6)和无病理(n = 6)患者中提取DNA,用核酸外切酶降解线性DNA,分离环状DNA。AD、PSP或健康对照脑的死后冷冻切片用于反转录转座子序列的荧光原位杂交(FISH)。在FISH组织上进行phospho - STING共免疫荧光。果蝇大脑也被用于反转录转座子的FISH。采用数字qPCR方法测定人和蝇组织中反转录转座子的拷贝数。结果初步数据显示,与对照组相比,阿尔茨海默病和PSP患者大脑中磷- STING水平升高。初步数据还表明,与对照组相比,tau病理中环状DNA测序中的反转录转座子DNA富集。结论反转录转座子衍生的ecdna可能是AD和PSP中cGAS - STING通路的激活因子。
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来源期刊
Alzheimer's & Dementia
Alzheimer's & Dementia 医学-临床神经学
CiteScore
14.50
自引率
5.00%
发文量
299
审稿时长
3 months
期刊介绍: Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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