Proteasome-dependent regulation of active zone proteins in activity-induced plasticity of presynaptic function

• Applicant: Professorin Dr. Anna Fejtová
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2012 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 217676110

Functional plasticity of neurotransmitter release is a cellular mechanism underlying complex brain functions such as learning and memory formation. Synaptic transmission is based on a precisely controlled sequence of molecular interactions and it is therefore plausible that the functional changes occurring during synaptic plasticity are connected with the molecular remodeling of involved synaptic machineries. The components of the cytomatrix at the active zone (CAZ) are involved in the spatial organization and functional regulation of the neurotransmitter release from the presynaptic boutons. Our previous studies have shown that activity-induced remodeling of the CAZ involves both de novo synthesis as well as ubiquitin-proteasome system- (UPS-) dependent degradation of CAZ proteins. This project is designed to study the cellular and molecular mechanisms controlling this UPS-dependent regulation of the CAZ and its role in activity-induced presynaptic plasticity. To this end will study the molecular interaction of CAZ proteins Bassoon and liprin-with ubiquitin-conjugating E3 enzymes and with subunits of the proteasome. We will investigate the role of these interactions in the regulation of UPS-dependent degradation of target proteins and consecutively in the modulation of presynaptic function. Moreover, we plan to perform imaging studies of activity-dependent modulation of proteasomal dynamic localization and processivity in axons and presynaptic boutons. This study will gain new insights into UPS-dependent mechanisms underlying activity-dependent remodeling of the CAZ during experience-induced and homeostatic synaptic plasticity.

• DFG Programme: Research Grants