Soma-yerelleştirilmiş Rab39, Atg9 veziküllerinin kaçakçılığını kontrol ederek sinaptik otofajiyi inhibe eder.

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Presynaptic terminals can be located far from the neuronal cell body and are thought to independently regulate protein and organelle turnover. Autophagy is a critical process for maintaining proteostasis, and its synaptic dysregulation is associated with neurodegenerative diseases. In this work, we report a soma-centered mechanism that regulates autophagy-controlled protein turnover at distant presynaptic terminals in Drosophila. We show that a central component of this system is Rab39, whose human homolog RAB39B is mutated in Parkinson's disease. Although Rab39 is localized in the soma, its loss of function or a human pathogenic mutation causes increased autophagy at presynaptic terminals, resulting in faster synaptic protein turnover and dopaminergic synapse degeneration. Using a large-scale unbiased genetic modifier screen, we identified genes encoding cytoskeletal and axonal organizing proteins, including Shortstop (Shot), as suppressors of synaptic autophagy. We demonstrate that active Rab39 selectively controls Shot- and Unc104/KIF1A-mediated delivery of autophagy-related Atg9-positive vesicles to synapses. Our findings suggest that Rab39-mediated trafficking in the soma orchestrates a cross-compartmental mechanism that regulates the levels of autophagy at synapses.

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