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

Patricia Kreis (), Christian Gallrein, Eugenia Rojas-Puente, Till G. A. Mack, Cristina Kroon, Viktor Dinkel, Claudia Willmes, Kai Murk, Susanne tom-Dieck, Erin M. Schuman, Janine Kirstein () and Britta J. Eickholt ()
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Patricia Kreis: Charité – Universitätsmedizin Berlin
Christian Gallrein: Leibniz-Research Institute for Molecular Pharmacology (FMP)
Eugenia Rojas-Puente: Charité – Universitätsmedizin Berlin
Till G. A. Mack: Charité – Universitätsmedizin Berlin
Cristina Kroon: Charité – Universitätsmedizin Berlin
Viktor Dinkel: Charité – Universitätsmedizin Berlin
Claudia Willmes: Charité – Universitätsmedizin Berlin
Kai Murk: Charité – Universitätsmedizin Berlin
Susanne tom-Dieck: Max Planck Institute for Brain Research
Erin M. Schuman: Max Planck Institute for Brain Research
Janine Kirstein: Leibniz-Research Institute for Molecular Pharmacology (FMP)
Britta J. Eickholt: Charité – Universitätsmedizin Berlin

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08420-w

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