Hsu, Chia-HengChia-HengHsuLi, Yi-JhanYi-JhanLiGuo, Ting-NiTing-NiGuoTzou, Fei-YangFei-YangTzouHong, Cheng-LiCheng-LiHongLin, Chin-HsienChin-HsienLinHuang, Shu-YiShu-YiHuangCHIH-CHIANG CHAN2025-12-122025-12-122025-08-05https://scholars.lib.ntu.edu.tw/handle/123456789/734597Autophagic decline accompanies age and causes a deterioration in proteostasis, rendering neuronal demise. Rab27 functions as a vesicle regulator for macroautophagic/autophagic degradation and exocytosis. Loss of in αβp brain neurons enhances longevity, underscoring its neuronal role and systemic effect. To understand the underlying mechanisms, we characterized the cell autonomous and non-autonomous functions of . expression increased in midlife, providing a temporal manipulation window. Depleting at that timepoint activated autophagy and sustained neuronal maintenance. At the organismic level, Egfr (Epidermal growth factor receptor) ligand was reduced and Akt kinase underphosphorylated in the KO fly body, indicating a widespread signaling cascade. Finally, KO ameliorates the neurotoxicity in a fly α-synucleinopathy model. Altogether, our results highlight a neuronal autophagy regulator exerting systemic effects that are crucial for neuronal maintenance and improving longevity.: Atg autophagy-related genes;EGF: epidermal growth factor; Egfr: Epidermal growth factor receptor;EGFR: epidermal growth factor receptor; foxo: forkhead box, sub-groupO; mTor: mechanistic target of rapamycin; MTOR: mechanistic target ofrapamycin; spi: spitz.enAutophagyEgfrRab27brain-fat body axislifespanparkinson disease[SDGs]SDG3journal article10.1080/15548627.2025.254138440765016