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We previously showed that the GGGGCC expanded repeats alone were sufficient to cause neurodegeneration in Drosophila. Recent evidence indicates that GGGGCC expanded repeats can modify various gene transcriptomes. To determine the role of these genes in GGGGCC-mediated neurotoxicity, we screened an established Drosophila model expressing GGGGCC expanded repeats in this study. Our results showed that knockdown of the DNA topoisomerase II (Top2) gene can specifically modulate GGGGCC-associated neurodegeneration of the eye. Furthermore, chemical inhibition of Top2 or siRNA-induced Top2 downregulation could alleviate the GGGGCC-mediated neurotoxicity in Drosophila assessed by eye neurodegeneration and locomotion impairment. By contrast, upregulated Top2 levels were detected in Drosophila strains, and moreover, TOP2A level was also upregulated in Neuro-2a cells expressing GGGGCC expanded repeats, as well as in the brains of Sod1G93A model mice. This indicated that elevated levels of TOP2A may be involved in a pathway common to the pathophysiology of distinct ALS forms. Moreover, through RNA-sequencing, a total of 67 genes, involved in the pathways of intracellular signaling cascades, peripheral nervous system development, and others, were identified as potential targets of TOP2A to modulate GGGGCC-mediated neurodegeneration.<\/jats:p>","DOI":"10.1093\/hmg\/ddab079","type":"journal-article","created":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T12:11:22Z","timestamp":1615810282000},"page":"893-901","source":"Crossref","is-referenced-by-count":8,"title":["Downregulation of <i>TOP2<\/i> modulates neurodegeneration caused by GGGGCC expanded repeats"],"prefix":"10.1093","volume":"30","author":[{"given":"Bin","family":"Jiao","sequence":"first","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China"},{"name":"Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA"},{"name":"National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan 410008, China"},{"name":"Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengli","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China"},{"name":"Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feiran","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junling","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China"},{"name":"National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan 410008, China"},{"name":"Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beisha","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China"},{"name":"National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan 410008, China"},{"name":"Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China"},{"name":"National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan 410008, China"},{"name":"Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"2021070819090977500_ref1","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1136\/jnnp-2015-312751","article-title":"Amyotrophic lateral sclerosis and motor neuron syndromes in Asia","volume":"87","author":"Shahrizaila","year":"2016","journal-title":"J. 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