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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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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