Preservation of cognitive function in ageing requires that both structural integrity and plasticity of involved synapses are maintained. Changes in pre- and postsynaptic structures, extracellular matrix (ECM) composition and perisynaptic astrocytic processes thus need to be delicately balanced, and deficits in this fine-tuned assembly will lead to functional decay and cognitive decline. ECM material deposited by both neurons and astrocytes thus accumulates in the ageing brain, leading to increased stiffness and endangering synaptic function. Both neurons and glia are able to sense such structural and mechanical changes through several sensors, including integrins and other cell adhesion molecules, cytoskeletal tension sensors such as filamin, as well as Piezo channels. However, little is known on the role of mechanotransduction in synaptic ageing, and the activation of intracellular signals such as the Hippo-YAP/TAZ pathway. Based on our preliminary data on the Hippo pathway kinase Ndr2 we propose that this pathway couples altered gene expression and proteostasis to synaptic function and thus forms a vicious cycle ultimately restraining synaptic function and plasticity in the aged brain.

Team project A2: Oliver Stork, Miguel Del Ángel, Allison Loaiza, Yunus Demiray

In project A2 we are testing this hypothesis using Ndr2 null mutant mice and examining the interaction of this gene product with activated mechanotransduction pathways in vivo and in vitro. We study effects of defined mechanical signals on neurite growth, synapse formation, transmission and plasticity as well as memory formation, and identify the intracellular factors that mediate the effects of Ndr2-dependent mechanotransduction on these processes.

Project A2: A. Loaiza, K. Jonischkies, J. Cerón, Y. Demiray, O. Stork

Find out more about the working group by clicking here.