Amyotrophic Lateral Sclerosis-associated GGGGCC repeat expansion promotes Tau phosphorylation and toxicity

Microtubule-associated protein Tau (MAPT) and GGGGCC (G₄C₂) repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) are the major known genetic causes of frontotemporal dementia (FTD) and other neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS). Although expanded G₄C₂ repeats and Tau traditionally are associated with different clinical presentations, pathological and genetic studies have suggested a strong association between them. Here we demonstrate a strong genetic interaction between expanded G₄C₂ repeats and Tau. We found that co-expression of expanded G₄C₂ repeats and Tau could produce a synergistic deterioration of rough eyes, motor function, life span and neuromuscular junction morphological abnormalities in Drosophila. Mechanistically, compared with the normal allele containing (G₄C₂)₃ repeats, the (G₄C₂)₃₀ allele increased Tau phosphorylation levels and promoted Tau R406W aggregation. These results together suggest a potential crosstalk between expanded G₄C₂ repeats and Tau in modulating neurodegeneration.