Volume 36, Issue. 12, December, 2020

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

Xue Wen 1 • Ping An 1 • Hexuan Li 1 • Zijian Zhou1  • Yimin Sun 1 • Jian Wang 1 • Lixiang Ma 2 • Boxun Lu 1

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 

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


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.



Browse: 60