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

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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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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Keywords

  • ALS
  • C9orf72
  • G4C2
  • Huntington disease