Active zone plasticity drives presynaptic dephosphorylation in Drosophila

ABSTRACT: The function of the nervous system relies on tightly regulated, yet plastic synaptic vesicle release machinery at the presynaptic active zone. In Drosophila, a form of presynaptic active zone plasticity, Presynaptic Scaling, or PreScale, is executed by the ELKS-family scaffold protein Bruchpilot (BRP), which drives the scaling of the Munc13 family release factors and other synaptic proteins. Genetic PreScale induction encodes sleep need and mediates early brain aging. However, the molecular mechanisms by which PreScale regulates sleep and brain aging remains unknown. Here, using an integrated-omics approach, we analyzed the proteome and phospho-proteome landscapes of genetic PreScale triggered by titrating brp gene copies from 1 to 4. Proteomic and bioinformatic analyses revealed changes in metabolic, immune, and stress responses pathways, as well as local translation control. Importantly, phospho-proteomic analysis showed BRP-induced PreScale provokes a global synaptic hypophosphorylation of proteins enriched for presynaptic components, suggesting a functional switch by reprogramming of the equilibrium of synaptic phosphorylation and dephosphorylation. Synaptic hypophosphorylation in PreScale is likely contributed by activity changes in Protein Kinase Aand the regulatory subunit of protein phosphatase 1 Spinophilin. We propose that synaptic hypophosphorylation might represent a typical molecular signature of PreScale in sleep homeostasis and brain aging, highlighting post-translation modifications in supporting long-term presynaptic plasticity.

INSTRUMENT(S):

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

TISSUE(S): Brain, Synapse Assembly

DISEASE(S): Sleep Disorder,Memory Impairment

SUBMITTER: Laxmikanth Kollipara  

LAB HEAD: Prof. Dr. Albert Sickmann

PROVIDER: PXD067034 | Pride | 2026-06-09

REPOSITORIES: Pride