Autophagy · 2026
Non-cell autonomous control of presynaptic remodeling by the hypothalamic autophagy-NPY axis.
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Cazzolla Giovanna, Toppe David, Krause Gina, Kochlamazashvili Gaga, Lützkendorf Janine, Schedina Ina M, Stephanowitz Heike, Reisenbichler Anna Maria, Chen Xingxiang, Kerkhoff Yannic, Reifenstein Eric, Ernst Helen M, von Kleist Max, Zimmermann Andreas, Eisenberg Tobias, Madeo Frank, Liu Fan, Herzog Herbert, Albrecht Anne, Schmitz Dietmar, Haucke Volker, Sigrist Stephan J, Maglione Marta
Аннотация
Macroautophagy/autophagy is a critical cellular degradation pathway essential for neuronal proteostasis and synaptic function. Its decline with aging is associated with synaptic dysfunction and reduced circuit resilience. NPY (neuropeptide Y), a highly abundant brain neuropeptide, has emerged as an important regulator of autophagy and aging-related processes. In Drosophila, the NPY-family peptide sNPF modulates age-related changes in presynaptic architecture via non-cell autonomous mechanisms. Here, we examined whether autophagy and NPY interact within hypothalamic NPY+ AGRP+ neurons to regulate presynaptic organization in distant brain regions. We show that autophagy in these neurons non-cell autonomously controls hippocampal presynaptic active zone architecture and proteostasis, while maintaining NPY peptide levels. Importantly, dietary supplementation of the natural polyamine spermidine restored NPY expression in the aged hippocampus, highlighting its potential to rejuvenate neuropeptide signaling. Together, these findings reveal a pathway by which hypothalamic autophagy and NPY signaling regulate hippocampal synaptic architecture, linking metabolic state to synaptic resilience.Abbreviations: AGRP: agouti related neuropeptide; ARC: arcuate nucleus; ATG5: autophagy related 5; AZ: active zone; BECN1/beclin1: beclin 1, autophagy related; brp: bruchpilot; BSN: bassoon; CA3-CA1: cornu ammonis 3-cornu ammonis 1; CACNA1A/CaV2.1: calcium channel, voltage-dependent, P/Q type, alpha 1A subunit; cKO: conditional knockout; gSTED: time-gated Stimulated Emission Depletion; HOMER1: homer scaffolding protein 1; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MB: mushroom body; MF-CA3: mossy fiber-cornus ammonis 3; NPY: neuropeptide Y; NPY1R: neuropeptide Y receptor Y1; NPY2R: neuropeptide Y receptor Y2; NPY5R: neuropeptide Y receptor Y5; PreScale: presynaptic upscaling; RIMBP2: RIMS binding protein 2; SQSTM1/p62: sequestosome 1; sNPF: short neuropeptide F precursor; SLC30A3/ZNT3: solute carrier family 30 (zinc transporter), member 3; Spd: spermidine; Spd-S: spermidine supplementation; WT: wild-type.