Tau gene structure-function relationships: how do genetic variations in the Tau gene MAPT influence Tau-mediated degeneration?

Abstract

The microtubule associated protein Tau plays a critical pathogenic role in multiple neurodegenerative diseases, called Tauopathies, which manifest as sporadic or familial dementias. Tauopathies have significant clinical, microscopic and molecular heterogeneity, which poses challenges for diagnosis and treatment. Tau hyperphosphorylation and aggregation are two hallmarks of Tauopathies and represent common therapeutic targets. However, the extent to which these mechanisms independently contribute towards neurotoxicity and drive disease heterogeneity remains unclear. 

Leveraging the genetic tractability of Drosophila, this thesis investigates the relative contributions of phosphorylation and aggregation towards Tau-mediated neurodegeneration. This was achieved by using novel designer human transgenes with altered phosphorylation status and/or aggregation propensity by deleting the ³⁰⁶VQIVYK³¹¹ motif. By assessing Tau accumulation, neurodegeneration, neuronal function and survival in the aging Drosophila nervous system, I evaluated the utility of ³⁰⁶VQIVYK³¹¹ as a therapeutic target through genetic deletion and pharmacological inhibition with RI-AG03 in vivo. 

This evaluation demonstrated that hyperphosphorylation-induced toxicity is dependent on the ³⁰⁶VQIVYK³¹¹ motif, where its deletion completely abolishes severe neurotoxicity, Tau accumulation, mis-localisation and functional deficits caused by phospho-mimicking Tau at 14 disease associated epitopes (TauE14). Studies to investigate the mechanisms underlying this rescue in toxicity imply that ³⁰⁶VQIVYK³¹¹ does not mediate protection by altering Tau’s microtubule binding ability or phosphorylation propensity. The rescue could also not be explained purely through a reduction of Tau aggregation as measured by the amount of insoluble Tau species formed in animals with and without the ³⁰⁶VQIVYK³¹¹ domain. However, using the conformation-specific MC1 antibody, my results indicate that ³⁰⁶VQIVYK³¹¹ may mediate toxicity by controlling the misfolding of Tau into pathogenic conformations. 

Furthermore, I show that ³⁰⁶VQIVYK³¹¹ represents a broad therapeutic target which can reduce toxicity not just of hyperphosphorylated Tau, but also of the disease-associated R406W mutant. Pharmacological inhibition using RI-AG03 selectively reduced the accumulation of phospho-mimicking Tau, showing good translation of in vivo efficacy, although optimisation of delivery and dose are needed. 

This thesis establishes ³⁰⁶VQIVYK³¹¹ as a central mediator of Tau toxicity across multiple pathological contexts and highlights a focal shift for future studies to design therapies that target pathological conformations rather than Tau aggregate abundance alone.

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Identifiers

ORCID for Amber Skye Cooper: orcid.org/0000-0003-2525-0148

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

ORCID for Herman Wijnen: orcid.org/0000-0002-8710-5176

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