216B Poster - 01. Cell Stress and cell death
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Rajan Thakur ¹; Kate O’Connor-Giles ^1,2

Affiliations:
1) Department of Neuroscience, Brown University, Providence, RI; 2) Carney Institute for Brain Science, Providence, RI

Keywords:
f. autophagy; f. neuromuscular junction

Sites of apposition between organelles, referred to as membrane contact sites (MCSs), are hotspots for intracellular signaling, lipid metabolism, and organelle biogenesis/dynamics in eukaryotic cells. The endoplasmic reticulum (ER) forms an extensive and dynamic network of MCSs with almost all organelles. MCSs between the ER and endo-lysosomes are particularly abundant, suggesting important physiological roles. PDZD8 is an intrinsic ER transmembrane protein with a synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain that has been reported to localize to ER-late endosome/lysosome and ER-mitochondria MCSs. PDZD8 is enriched in neurons. However, its role in the nervous system remains poorly understood. We identified Drosophila PDZD8 in a candidate screen for uncharacterized conserved regulators of synapse formation and function. We used the CRISPR-Cas9 system to generate null alleles and endogenously tag PDZD8. Interestingly, we find that PDZD8 is expressed at synapses throughout the central nervous system and the larval neuromuscular junction (NMJ), where it localizes to ER-lysosome MCSs. We show that activity-induced synaptic growth, neurotransmission, and locomotion are dysregulated in PDZD8 mutants, indicating important roles in nervous system development and function. We further show that PDZD8 regulates synaptic growth via autophagy. In PDZD8 mutants we see accumulation of autophagic proteins as well as autolysosomes. Our analyses suggest that PDZD8 is required for autolysosome maturation to promote autophagic flux in neurons.Overall, we propose that PDZD8-mediated ER-lysosome membrane interactions promote autophagy to regulate synaptic growth.