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. •Co-expression of expanded G4C2 repeats and Tau causes synergistic neuronal toxicity in Drosophila.•Expanded rG4C2 repeats alters the phosphorylation of Tau.•Co-expression of expanded G4C2 repeats and Tau led to an increase in CDK5 phosphorylation.•Expanded rG4C2 repeats alters the solubility of Tau.