ATM phosphorylation of the actin-binding protein drebrin controls oxidation stress-resistance in mammalian neurons and C. elegans

Patricia Kreis,Erin M Schuman,Cristina Kroon,Till G A Mack,Susanne Tom-Dieck,Kai Murk,Viktor Dinkel,Britta J Eickholt,Eugenia Rojas-Puente,Janine Kirstein,Christian Gallrein,Claudia Willmes

doi:10.1038/s41467-019-08420-w

Patricia Kreis, Erin M Schuman + Show 10 more

Open Access

https://doi.org/10.1038/s41467-019-08420-w

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Abstract

Drebrin (DBN) regulates cytoskeletal functions during neuronal development, and is thought to contribute to structural and functional synaptic changes associated with aging and Alzheimer’s disease. Here we show that DBN coordinates stress signalling with cytoskeletal dynamics, via a mechanism involving kinase ataxia-telangiectasia mutated (ATM). An excess of reactive oxygen species (ROS) stimulates ATM-dependent phosphorylation of DBN at serine-647, which enhances protein stability and accounts for improved stress resilience in dendritic spines. We generated a humanized DBN Caenorhabditis elegans model and show that a phospho-DBN mutant disrupts the protective ATM effect on lifespan under sustained oxidative stress. Our data indicate a master regulatory function of ATM-DBN in integrating cytosolic stress-induced signalling with the dynamics of actin remodelling to provide protection from synapse dysfunction and ROS-triggered reduced lifespan. They further suggest that DBN protein abundance governs actin filament stability to contribute to the consequences of oxidative stress in physiological and pathological conditions.

Highlights

Drebrin (DBN) regulates cytoskeletal functions during neuronal development, and is thought to contribute to structural and functional synaptic changes associated with aging and Alzheimer’s disease
This result indicates that reducing the level of DBN affects F-actin content in dendritic spines, a process that is unmasked by low concentrations of LatB
The major finding from this study is the identification of DBN as an ataxia-telangiectasia mutated (ATM) substrate and of a mechanism to protect against oxidative stress-induced cellular dysfunction

Summary

Introduction

Drebrin (DBN) regulates cytoskeletal functions during neuronal development, and is thought to contribute to structural and functional synaptic changes associated with aging and Alzheimer’s disease. Our data indicate a master regulatory function of ATM-DBN in integrating cytosolic stress-induced signalling with the dynamics of actin remodelling to provide protection from synapse dysfunction and ROS-triggered reduced lifespan. They further suggest that DBN protein abundance governs actin filament stability to contribute to the consequences of oxidative stress in physiological and pathological conditions. Drebrin (developmentally regulated brain protein, DBN) is a conserved F-actin side-binding protein that reduces actin filament turnover[1,2,3] It is enriched in dendritic spines, where it is thought to control spine morphology and function[4]. We set out to explore here if cellular insult, stress, or ageing renders neurons vulnerable to DBN-loss

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