The Role of Presynaptic Par-1 Kinase in Regulating the Localization of Active Zone Protein BRP

Precise localization of synaptic proteins is required for proper synaptic function, which is compromised in many neurodevelopmental and neurodegenerative diseases. Since proteins that reside at the active zones are used most frequently during synaptic transmission, they must be continuously replenished to maintain active zones. Therefore, the trafficking of these proteins plays an essential role in replenishing these vital components necessary for the health of active zones. While the trafficking and localization of synaptic vesicles and mitochondria are relatively well understood, little is known about the mechanisms that regulate the localization of protein components localized to active zones. In this dissertation, I show that mechanisms involved in transporting proteins destined to active zones are distinct from those that transport synaptic vesicles or mitochondria. Further, imprecise levels of presynaptic Par-1 kinase disrupt the transport of Bruchpilot- an essential active zone scaffolding protein in Drosophila and leads to its accumulation of BRP in axons at the expense of BRP at active zones. Ultimately, the loss of BRP at active zones results in reduced synaptic transmission. Temporal analysis demonstrated that accumulation of BRP within the axons precedes the loss of synaptic function and its depletion from the active zones. Mechanistically, my data suggest that Par-1 co-localizes with BRP and is present in the same complex as BRP, raising the possibility of a novel mechanism for selective localization of BRP. Taken together, these data suggest an intriguing possibility that mislocalization of active zone proteins like BRP might be one of the earliest signs of perturbation of synapses that precede many neurological disorders.