PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth

PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth

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Summary: Building synaptic connections requires coordinating a host of cellular activities from cell signaling to protein turnover, placing a high demand on intracellular communication.Membrane contact sites (MCSs) formed between organelles have emerged as key signaling hubs for coordinating diverse Plein air - Homme - Chaussures - Soulier cellular activities, yet their roles in the developing nervous system remain obscure.We investigate the in vivo function of the endoplasmic reticulum (ER) MCS tethering and lipid-transfer protein PDZD8, which was recently linked to intellectual disability, in the nervous system.We find that PDZD8 is required for activity-dependent synaptic bouton formation in multiple paradigms.

PDZD8 is sufficient to drive excess synaptic bouton formation through an autophagy-dependent mechanism and required for synapse development when autophagy is limited.PDZD8 accelerates autophagic flux by promoting 332 lysosome maturation at ER-late endosome/lysosome MCSs.We propose that PDZD8 functions in the nervous system to increase autophagy during periods of high demand, including activity-dependent synaptic growth.