The cell autonomous and non-autonomous functions of Rab27 in longevity and neuroprotection in <i>Drosophila</i>

Autophagic 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 <i>Drosophila Rab27</i> 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 <i>Rab27</i>. <i>Rab27</i> expression increased in midlife, providing a temporal manipulation window. Depleting <i>Rab27</i> 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 <i>Rab27</i> KO fly body, indicating a widespread signaling cascade. Finally, <i>Rab27</i> 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. <b>Abbreviation</b>: 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