Project Details
Projekt
Interdependencies of autophagy, protein synthesis, aging, activity and synaptic viability.
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 447288260
Synapses in the brain can persist for months and even years. Their proteinaceous components, however, become dysfunctional after much shorter periods, and thus must be continuously removed and degraded. Autophagy is one such removal pathway, mainly involved in clearance of protein complexes and aggregates. Significant evidence suggests that aging is associated with impaired protein clearance, and that manipulations that augment autophagy increase life-span and rejuvenate multiple physiological processes including several pertaining to synaptic and cognitive functions. As a rule, catabolic and anabolic processes are tightly coupled, and thus manipulations that enhance autophagy are likely to affect other aspects of protein metabolism, in particular protein synthesis. Our goal here is, thus, to gain a broader view of the effects exerted by such manipulations, using them to expose interdependencies among autophagy, protein synthesis, aging, activity, and synaptic viability. To that end we will examine how spermidine and its derivative hypusine impact (synaptic) protein synthesis and degradation in standard and aged neuronal cultures, in mice of different ages, and in mice raised in enriched environments. Long-term imaging will be used to examine how these manipulations affect autophagic flux, neuronal viability, synaptic persistence, tenacity and function, as well as resilience to stressors, in standard and aged neuronal cultures. Finally, we will use the obtained data to identify autophagy-associated druggable targets that might improve life-long neuronal and synaptic viability, and then, in collaboration with other FOR groups, test a subset of these. We expect that these findings will provide new insights on relationships among autophagy, protein synthesis, aging, activity and synaptic viability, and possibly uncover targets for useful pharmacological interventions.
DFG Programme
Research Units
International Connection
Israel
