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

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 ³⁰⁶VQIVYK³¹¹ 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.

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Identifiers

ORCID for Ben Batchelor: orcid.org/0009-0009-6722-9874

ORCID for Miguel Ramírez Moreno: orcid.org/0000-0003-1559-8976

ORCID for George Devitt: orcid.org/0000-0001-7179-4459

ORCID for Amritpal Mudher: orcid.org/0000-0002-0880-1107

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