Non-cell autonomous control of presynaptic remodeling by the hypothalamic autophagy/NPY axis

Cazzolla, G.; Toppe, D.; Krause, G.; Kochlamazashvili, G.; Luetzkendorf, J.; Schedina, I. M.; Kerkhoff, Y.; Reifenstein, E.; von Kleist, M.; Herzog, H.; Albrecht, A.; Schmitz, D.; Haucke, V.; Sigrist, S. J.; Maglione, M.

doi:10.1101/2025.06.20.660653

bioRxiv · 10.1101/2025.06.20.660653

Non-cell autonomous control of presynaptic remodeling by the hypothalamic autophagy/NPY axis

Cazzolla, G.·Toppe, D.·Krause, G.·Kochlamazashvili, G.·Luetzkendorf, J.·Schedina, I. M.·Kerkhoff, Y.·Reifenstein, E.·von Kleist, M.·Herzog, H.·Albrecht, A.·Schmitz, D.·Haucke, V.·Sigrist, S. J.·Maglione, M.

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Abstract

Macroautophagy/autophagy, a critical cellular degradation pathway essential for maintaining neuronal proteostasis, declines with age and has been increasingly implicated in the regulation of synaptic integrity and circuit resilience. Neuropeptide Y (NPY), the most abundantly expressed neuropeptide in the mammalian brain, has emerged as a key modulator of both autophagy and aging-related processes. In Drosophila, the NPY-family peptide short Neuropeptide F (sNPF) has been shown to causally influence aging-associated changes in synaptic architecture and function, particularly at the presynaptic active zone (AZ), via non-cell autonomous mechanisms. Extending this concept to mammals, we investigated whether NPY and autophagy interact within NPY-secreting neurons to regulate age-related AZ remodeling. Our results indicate that hypothalamic NPY/AgRP neurons may exert geroprotective effects through the release of NPY and potentially other signaling molecules, thereby influencing both metabolic homeostasis and brain-wide synaptic function. These data suggest a conserved role for autophagy in maintaining presynaptic organization and resilience during aging.

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Cazzolla, G., Toppe, D., Krause, G., Kochlamazashvili, G., Luetzkendorf, J., Schedina, I. M., Kerkhoff, Y., Reifenstein, E., von Kleist, M., Herzog, H., Albrecht, A., Schmitz, D., Haucke, V., Sigrist, S. J., Maglione, M.. 2025-06-22. Non-cell autonomous control of presynaptic remodeling by the hypothalamic autophagy/NPY axis. https://doi.org/10.1101/2025.06.20.660653

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