Molecular and Functional Integration of Neuronal Autophagy and Presynaptic Remodeling
MARTA MAGLIONE (Freie Universität, Berlin)
STEPHAN J. SIGRIST (Freie Universität, Berlin)
Synaptic stability and plasticity depend on the dynamic coordination of membrane recycling, proteostasis, and molecular remodeling. Resilience—the brain’s ability to adapt to stressors such as sleep deprivation—declines with age and is thought to involve sleep homeostasis, neuronal excitability, and metabolic integrity. However, how these processes are mechanistically linked remains poorly understood. Our data suggest that autophagy in central integrative centers, the mushroom body (MB) in Drosophila and the hypothalamus in mice, may act as a key regulator of brain-wide synaptic resilience.
In Drosophila, early autophagy inhibition in the MB extends lifespan and is accompanied by widespread changes in presynaptic active zones (AZs), including scaffold protein accumulation and altered ion channel expression. These changes coincide with increased sleep and may reflect a resilience-promoting state. In mice, hypothalamic autophagy appears to influence hippocampal synapses via neuropeptide Y (NPY) signaling and polyamine metabolism, pointing to a conserved mechanism linking energy sensing, proteostasis, and synaptic plasticity.
Here we combine genetic, imaging, proteomic, and behavioral approaches in flies and mice to dissect how autophagy coordinates presynaptic remodeling, and how these processes contribute to synaptic resilience. We aim to define conserved signaling modules that support brain-wide plasticity during aging and stress.
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