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Tau Accumulation via Reduced Autophagy Mediates GGGGCC Repeat Expansion-Induced Neurodegeneration in Drosophila Model of ALS

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Abstract

Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders, including Huntington disease [caused by expanded CAG repeats (CAGr) in the HTT gene], and amyotrophic lateral sclerosis [ALS, possibly caused by expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene], of which the molecular mechanisms remain unclear. Here, we demonstrated that lowering the Drosophila homologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r. Expression of human tau (htau4R) restored the disease-related phenotypes that had been mitigated by the loss of dtau, suggesting an evolutionarily-conserved role of tau in neurodegeneration. We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome–lysosome fusion, possibly due to lowering the level of BAG3, a regulator of autophagy and tau. Taken together, our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism. Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.

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Acknowledgements

We thank Prof. Peng Jin and Ranhui Duan for providing the G4C2 Drosophila, Prof. L. Partridge, Haihuai He, and Peng Lei for providing the dtau-knockout Drosophila, Prof. Yongqin Zhang for providing related tool Drosophila stocks and UAS-htau4R [28], and Prof. Shouqing Luo for providing the Lamp1-mcherry vector. This work was supported by the National Natural Science Foundation of China (81925012 and 31961130379) and a Newton Advanced Fellowship (NAF_R1_191045).

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  1. Xue Wen and Ping An have contributed equally to this work.

Authors and Affiliations

  1. Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Xue Wen, Ping An, Hexuan Li, Zijian Zhou, Yimin Sun, Jian Wang & Boxun Lu

  2. Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Lixiang Ma

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  1. Xue Wen
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Wen, X., An, P., Li, H. et al. Tau Accumulation via Reduced Autophagy Mediates GGGGCC Repeat Expansion-Induced Neurodegeneration in Drosophila Model of ALS. Neurosci. Bull. 36, 1414–1428 (2020). https://doi.org/10.1007/s12264-020-00518-2

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