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.
Electronic supplementary materialThe online version of this article (10.1007/s12264-020-00518-2) contains supplementary material, which is available to authorized users.
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