# Mutant Tau (P301L) Enhances Global Protein Translation in Differentiated SH-SY5Y Cells by Upregulating mTOR Signalling

## TL;DR

A specific Tau mutation increases overall protein production in nerve-like cells by boosting a key signaling pathway, which could worsen brain diseases like Alzheimer's.

## Contribution

The study reveals that mutant Tau (P301L) enhances global protein translation via mTOR signaling in human-derived neurons.

## Key findings

- Tau-P301L overexpression significantly increases global protein synthesis in SH-SY5Y cells.
- The increase in translation is mediated through upregulation of the mTOR/S6 pathway.
- Rapamycin treatment reverses the translational upregulation caused by mutant Tau.

## Abstract

Altered protein synthesis plays a key role in ageing and multiple neurodegenerative diseases. In Alzheimer’s disease and other tauopathies, the intracellular accumulation of hyperphosphorylated Tau disrupts several cellular processes, including mRNA translation. Although Tau interacts with ribosomal proteins and modulates translational selectivity, its effects on global protein synthesis remain poorly understood. Studies report reduced translation in later disease stages but increased translation early in pathology. To clarify Tau’s impact in human neurons, we used SH-SY5Y cells overexpressing the P301L mutant form of Tau and quantified global protein synthesis using the SUnSET (Surface Sensing of Translation) puromycin-incorporation assay. We found that Tau-P301L expression greatly increased global translation by upregulating mTOR/S6 pathway. These effects were abolished by rapamycin treatment, indicating that Tau-driven translational upregulation is mTOR-dependent. Given that impaired translational control can disrupt synaptic plasticity and memory, Tau-induced alterations in protein synthesis may contribute to tauopathy progression and identify mTOR signalling as a potential therapeutic target.