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<p>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 <i>Drosophila</i>. 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.</p>

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Soma-localized Rab39 inhibits synaptic autophagy by controlling trafficking of Atg9 vesicles

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月21日

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  • Ayse Kilic,
  • Gokhan Ozturan,
  • Dirk Vandekerkhove,
  • Sabine Kuenen,
  • Jef Swerts,
  • Esther Muñoz Pedrazo,
  • Carles Calatayud Aristoy,
  • Abril Escamilla Ayala,
  • Nikky Corthout,
  • Pablo Hernández Varas,
  • Stéphane Plaisance,
  • Valerie Uytterhoeven,
  • Eliana Nachman,
  • Patrik Verstreken

摘要

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.