Amyotrophic Lateral Sclerosis-associated GGGGCC repeat expansion promotes Tau phosphorylation and toxicity

Hua He; Wen Huang; Ruoxi Wang; Yunting Lin; Yichen Guo; Jing Deng; Haitao Deng; Yanping Zhu; Emily G. Allen; Peng Jin; Ranhui Duan

Neurobiology of Disease (Oct 2019)

Amyotrophic Lateral Sclerosis-associated GGGGCC repeat expansion promotes Tau phosphorylation and toxicity

Hua He,
Wen Huang,
Ruoxi Wang,
Yunting Lin,
Yichen Guo,
Jing Deng,
Haitao Deng,
Yanping Zhu,
Emily G. Allen,
Peng Jin,
Ranhui Duan

Affiliations

Hua He: Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Wen Huang: Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Ruoxi Wang: Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Yunting Lin: Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Yichen Guo: Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Jing Deng: Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Haitao Deng: Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Yanping Zhu: Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Emily G. Allen: Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA
Peng Jin: Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA; Corresponding authors.
Ranhui Duan: Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China; Corresponding authors.

Journal volume & issue: Vol. 130
p. 104493

Abstract

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Microtubule-associated protein Tau (MAPT) and GGGGCC (G4C2) repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) are the major known genetic causes of frontotemporal dementia (FTD) and other neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS). Although expanded G4C2 repeats and Tau traditionally are associated with different clinical presentations, pathological and genetic studies have suggested a strong association between them. Here we demonstrate a strong genetic interaction between expanded G4C2 repeats and Tau. We found that co-expression of expanded G4C2 repeats and Tau could produce a synergistic deterioration of rough eyes, motor function, life span and neuromuscular junction morphological abnormalities in Drosophila. Mechanistically, compared with the normal allele containing (G4C2)3 repeats, the (G4C2)30 allele increased Tau phosphorylation levels and promoted Tau R406W aggregation. These results together suggest a potential crosstalk between expanded G4C2 repeats and Tau in modulating neurodegeneration.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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