Ageing, proteotoxic stress and the neuronal cytoskeleton: Analyses of the age-dependent challenges of the actin filament system

• Applicants: Professorin Dr. Britta Eickholt; Professorin Dr. Janine Kirstein
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 285933818

The actin binding protein Drebrin (DBN) regulates cytoskeletal functions during neuronal development, and is thought to contribute to structural and functional synaptic changes associated with ageing and Alzheimer’s disease. In the previous funding period we identified 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 DBN stability and accounts for improved stress resilience in dendritic spines. In order to investigate how DBN phosphorylation and abundance affects systemic ageing, we generated a humanized DBN Caenorhabditis elegans (C. elegans) model. Using this system, we identified that blocking DBN serine-647 phosphorylation (using a DBNS647A variant) disrupts protective ATM signalling on lifespan under sustained oxidative stress. Our combined data indicate an important regulatory function of ATM-DBN in integrating cytosolic ROS-induced signalling with the dynamics of actin remodelling to provide protection from synapse dysfunction and ROS-triggered reduced lifespan. In this collaborative research proposal by the Eickholt lab in Berlin and the Kirstein lab in Bremen (following her move from Berlin), we propose to investigate if actin filament dynamics more generally can safeguard neurons from proteotoxicity as well as neurodegenerative diseases. The Eickholt lab will perform critical experiments in mice, and analyse the actin cytoskeleton and neuronal function with ageing, and in response to Abeta1-42 and oxidative stress. The Kirstein lab will exploit the nematode system to gain insight into the regulatory circuits controlling DBN and study its protection against Abeta1-42 aggregation and toxicity upon perturbation of the actin cytoskeleton or in response to oxidative stress. In combination, the work will provide mechanistic as well as physiological insights into the functional role of the actin cytoskeleton to provide neuronal protection upon stress neurodegeneration and with the progression of ageing.

• DFG Programme: Research Grants