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

• 来源期刊: 神经科学通报（英文版）
• 年，卷（期）: 2020,（12）
• 所属期刊栏目: Original Articles
• 页码范围: 1414-1428
• 页数: 15页
• 语种: 英文

摘要

Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders,includ-ing 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 evolu-tionarily-conserved mechanism.Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.