Aggregation promoting sequences rather than phosphorylation are essential for Tau-mediated toxicity in Drosophila

Cooper, A.; Richardson, B.; Ruiz Ortega, E.; Zhang, Y.; Batchelor, B.; Vaikakkara Chithran, A.; Liu, J.; Lian, T.; Ramirez Moreno, M.; Boehme, B.; Abtahi, S.; Devitt, G.; Sivanantharajah, L.; Skoulakis, E. M. C.; Allan, D. W.; Mudher, A.

doi:10.1101/2024.12.22.629946

bioRxiv · 10.1101/2024.12.22.629946

Aggregation promoting sequences rather than phosphorylation are essential for Tau-mediated toxicity in Drosophila

Cooper, A.·Richardson, B.·Ruiz Ortega, E.·Zhang, Y.·Batchelor, B.·Vaikakkara Chithran, A.·Liu, J.·Lian, T.·Ramirez Moreno, M.·Boehme, B.·Abtahi, S.·Devitt, G.·Sivanantharajah, L.·Skoulakis, E. M. C.·Allan, D. W.·Mudher, A.

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Abstract

BackgroundDisease-modifying therapies for tauopathies like Alzheimers 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. MethodsLeveraging 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. ResultsWe report that phospho-mimicking Tau (hTau2N4RE14) induced profound neurodegeneration, supporting a neurotoxic role for phosphorylation. However, when we rendered hTau2N4RE14 aggregation incompetent, by deleting the 306VQIVYK311 motif in the microtubule-binding region, neurotoxicity was abolished. Moreover, a peptide inhibitor targeting this motif efficaciously reduced Tau toxicity in aging Drosophila. ConclusionNeurodegeneration 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.

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Cooper, A., Richardson, B., Ruiz Ortega, E., Zhang, Y., Batchelor, B., Vaikakkara Chithran, A., Liu, J., Lian, T., Ramirez Moreno, M., Boehme, B., Abtahi, S., Devitt, G., Sivanantharajah, L., Skoulakis, E. M. C., Allan, D. W., Mudher, A.. 2024-12-23. Aggregation promoting sequences rather than phosphorylation are essential for Tau-mediated toxicity in Drosophila. https://doi.org/10.1101/2024.12.22.629946

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