Superresolution imaging and therapeutic targeting of extracellular matrix-mediated signalling in brain diseases
Numerous brain pathologies derive from synapse dysfunction (also known as synaptopathies). Considerable data have been accumulated regarding the role of pre- and postsynaptic molecules but very little is known how the extracellular matrix (ECM) affects the progression of synaptopathies, even though ECM molecules are strongly implicated in synaptic plasticity as well as in learning and memory. In this project, we will break new ground by investigating the (patho-)physiological functions of several prominent ECM molecules in the context of epilepsy and Alzheimer's disease (AD). Specifically, we will focus on the role of LGI1 (leucine-rich, glioma-inactivated 1) for epileptogenesis, and the role of heparan sulfate proteoglycans (HSPGs) and integrins for AD. LGI1 is strongly linked to human epilepsy and associates with pre- and postsynaptic proteins, suggesting a central role in the coordination of pre- and postsynaptic differentiation and signaling. HSPGs and integrins are major molecules involved in ECM-mediating signaling, and targeting these molecules may provide an effective strategy for counteracting synaptopathies. Hence, we aim to develop imaging probes and techniques to visualize modifications of ECM and synaptic structures during the progression of these two forms of synaptopathies. As synapses are very small, we will use superresolution STED (stimulated emission depletion) imaging of ECM and synaptic markers and combine it with FRET (Frster resonance energy transfer) measurements to monitor ECM-mediated signaling at synapses. To target the ECM, we propose to introduce reagents mimicking and stabilizing LGI1 and controlling aggregation and internalization of ?-Amyloid peptide (A?? and HSPGs, providing a powerful new handle to study the basic mechanisms of epilepsy and AD and to develop effective therapies. Beyond epilepsy and AD, the approaches developed during this project are likely to find much broader applications for the understanding and treatment of synaptopathies.
Gene targeting in the brain, Computational neurosciences, Molecular modelling techniques, Neuroinformatics, Imaging techniques, Pharmacology, Electrophisiological approaches, Behavioural methodologies, Extracellular matrix; Homeostatic regulations; Synaptic plasticity; Epilepsy; Neurodegeneration; Molecular and (epi)genetic and "omics" approaches
2013 - 2016
Alexander Dityatev (Coordinator)