Tau's Three-Repeat Domain and EFhd2 Co-incubation Leads to Increased Thioflavin Signal.

Irving E. Vega,Alexandra Sutter,Luke Parks,Magdalena I. Ivanova,Andrew Umstead

doi:10.3389/fnins.2018.00879

Irving E. Vega, Alexandra Sutter + Show 3 more

Open Access

https://doi.org/10.3389/fnins.2018.00879

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Abstract

Aggregation of the protein tau is a pathological hallmark of Alzheimer’s disease (AD) and related disorders. However, the molecular mechanisms that lead to tau protein aggregation are still unclear. Previously, we showed that EFhd2 protein is associated with pathological aggregated forms of tau in AD brain. Further, immuno-gold analyses of purified tau aggregates showed that EFhd2 co-localized with filamentous tau structures. We demonstrated that EFhd2’s coiled-coil domain is required for its association with tau proteins. However, it is unknown the role that EFhd2 plays in tau aggregation. Here, we show that incubation of K19-tau with substoichiometric amount of EFhd2 promote the formation of amyloid structures in vitro. The result suggests that EFhd2 may play a role in the biogenesis of aggregated tau.

Highlights

The accumulation of aggregated tau is a pathological hallmark of Alzheimer’s disease (AD) and related dementias (Chong et al, 2018)
To determine if EFhd2 association with tau can promote the formation of amyloid structures, we incubated K19 tau with substoichiometric concentrations of recombinant EFhd2 protein
We demonstrate, for the first time, that co-incubation of K19-tau with substoichiometric concentrations of EFhd2 proteins increases the formation of amyloid structures as detected by ThS fluorometry

Summary

Introduction

The accumulation of aggregated tau is a pathological hallmark of Alzheimer’s disease (AD) and related dementias (Chong et al, 2018). The molecular mechanisms that lead to tau aggregation are poorly understood. The accumulation of aberrant phosphorylated tau may promote the formation of specific conformations that render the protein prone to aggregation. Other posttranslational modifications, such as truncation, glycosylation, methylation, oxidation, have been associated with the formation of tau aggregates (Mietelska-Porowska et al, 2014). Mutations on tau gene (MAPT) render tau proteins prone to aggregation (Bodea et al, 2016). Molecular events that promote conformational changes may play a crucial role in the formation pathological tau species

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