Proteostasis & synaptic homeostasis

While many synapses live for decades, the proteins that determine synaptic function have half-lives of hours to days. On the one hand, this allows for plastic changes during development and learning. On the other hand, this poses the question of how stable synaptic transmission and neural function can be achieved and maintained at all. Synaptic function is tightly linked to the specific composition and abundance of proteins at synapses. However, the molecular pathways underlying the homeostatic control of proteins at synapses, or synaptic proteostasis, are largely unknown.

The main objective of this project is to unravel the molecular signaling systems underlying synaptic proteostasis through local protein degradation, and it’s role in homeostatic control of a key step in synaptic transmission – neurotransmitter release.

We recently uncovered a central role for local presynaptic proteostasis in the homeostatic control of neurotransmitter release, and linked two genes, including the schizophrenia-susceptibility gene dysbindin, to this form of regulation (Wentzel et al., 2018). We are in the process of concluding a study in which we systematically investigated the role of E3 ligases, a class of enzymes regulating protein degradation, in the homeostatic control of release through an electrophysiology-based genetic screen.