Local autophagy impairment triggers brain-wide presynaptic remodeling and resilience

Abstract Neural circuits must remain functionally stable while adapting to changing demands and levels of stress. While this balance is thought to rely on plasticity programs integrating molecular and activity-dependent signals, mechanistic models of how such adaptations are orchestrated remain limited. Here, we show that impairment of autophagy in the Drosophila mushroom body (MB) induces brain-wide, post-transcriptional remodeling of presynaptic active zones, characterized by increased expression levels of active zone scaffold proteins, reduced abundance of calcium channel subunits, and elevated levels of Shaker-type potassium channels. This remodeling promotes organismal resilience, as reflected by increased sleep and extended lifespan. Mechanistically, early-life activation of this program is sufficient to extend lifespan, identifying synaptic remodeling as a causal driver of adaptive responses. MB-specific autophagy disruption further leads to non-cell autonomous accumulation of autophagic substrates across the brain, consistent with a system-level proteostatic imbalance in which degradative pathways remain active, but appear insufficient to match cargo load. Our findings identify autophagy in the mushroom body as a key regulator of brain-wide synaptic architecture and resilience, and establish a genetically tractable model for how local proteostatic impairment can trigger adaptive, system-level circuit remodeling.