Identification of an ERK Inhibitor as a Therapeutic Drug Against Tau Aggregation in a New Cell-Based Assay.

Giacomo Siano,Giuseppe Madaro,Antonino Cattaneo,Valentina Quercioli,Maria Claudia Caiazza,Martina Varisco,Mariantonietta Calvello,Cristina Di Primio,Ivana Ollà

doi:10.3389/fncel.2019.00386

Giacomo Siano, Giuseppe Madaro + Show 7 more

Open Access

https://doi.org/10.3389/fncel.2019.00386

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Abstract

Formation of Tau aggregates is a common pathological feature of tauopathies and their accumulation directly correlates with cytotoxicity and neuronal degeneration. Great efforts have been made to understand Tau aggregation and to find therapeutics halting or reversing the process, however, progress has been slowed due to the lack of a suitable method for monitoring Tau aggregation. We developed a cell-based assay allowing to detect and quantify Tau aggregation in living cells. The system is based on the FRET biosensor CST able to monitor the molecular dynamic of Tau aggregation in different cellular conditions. We probed candidate compounds that could block Tau hyperphosphorylation. In particular, to foster the drug discovery process, we tested kinase inhibitors approved for the treatment of other diseases. We identified the ERK inhibitor PD-901 as a promising therapeutic molecule since it reduces and prevents Tau aggregation. This evidence establishes the CST cell-based aggregation assay as a reliable tool for drug discovery and suggests that PD-901 might be a promising compound to be tested for further preclinical studies on AD.

Highlights

Tauopathies are complex multifactorial diseases (Lee et al, 2001; Wang and Mandelkow, 2016) and, up to now, despite strong efforts, the drug discovery process has been inconclusive
The binding to MTs induces the folding of the Conformational Sensitive Tau (CST) into a loop-like conformation that brings the fluorophores close together generating the FRET signal; on the contrary, upon aggregation it detaches from MTs and forms
We developed a cell-based assay allowing to detect and quantify Tau aggregation in living cells

Summary

Introduction

Tauopathies are complex multifactorial diseases (Lee et al, 2001; Wang and Mandelkow, 2016) and, up to now, despite strong efforts, the drug discovery process has been inconclusive. Current approaches for the treatment of these pathologies do not rely on disease modifying drugs but rather on symptomatic treatments with the aim of attenuating and delaying behavioral degeneration (Birks, 2006; Wang and Reddy, 2017) These treatments cannot halt the progress of the pathology and the scientific community is working on therapeutic approaches aimed at preventing the development and progression of neurodegeneration by targeting the toxic amyloidogenic aggregates (Devos et al, 2017; West et al, 2017; Novak et al, 2019). PD-901 is a potent inhibitor of ERK pathway since it inhibits MEK1 and MEK2 preventing the activation of ERK (Barrett et al, 2008; Henderson et al, 2011; Yap et al, 2011) It is currently in clinical trial for the treatment of lung cancer and solid tumors (ClinicalTrials.gov Identifier: NCT02022982; NCT02039336; NCT03905148). D-JNKI-1 is a cell-penetrating peptide that inhibits JNK pathway (Hirt et al, 2004; Milano et al, 2007) and it is currently in clinical trial for the treatment of acute hearing loss (ClinicalTrials.gov Identifier: NCT02809118; NCT02561091)

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