bioRxiv · Dec 23, 2024
Aggregation promoting sequences rather than phosphorylation are essential for Tau-mediated toxicity in Drosophila
By Cooper AS, Richardson B, Ruiz E et al.
Abstract Background Disease-modifying therapies for tauopathies like Alzheimer’s disease have targeted Tau hyperphosphorylation and aggregation, as both pathological manifestations are implicated in Tau-mediated toxicity. However, the relative contributions of these pathology-linked changes to Tau neurotoxicity remain unclear. Methods Leveraging the genetic tractability of Drosophila , we generated multiple inducible human Tau transgenes with altered phosphorylation status and/or aggregation propensity. Their individual and combined impact was tested in vivo by quantifying Tau accumulation and neurodegenerative phenotypes in the aging fly nervous system. Results We report that phospho-mimicking Tau (hTau2N4R E14 ) induced profound neurodegeneration, supporting a neurotoxic role for phosphorylation. However, when we rendered hTau2N4R E14 aggregation incompetent, by deleting the 306 VQIVYK 311 motif in the microtubule-binding region, neurotoxicity was abolished. Moreover, a peptide inhibitor targeting this motif efficaciously reduced Tau toxicity in aging Drosophila . Conclusion Neurodegeneration mediated by Tau hyperphosphorylation is gated via at least one aggregation-mediating motif on the protein. This highlights the primacy of blocking Tau aggregation in therapy, perhaps without the need to clear phosphorylated species.