Autophagic Lysosome Reformation

Two phenomena have driven a recent interest in deciphering trafficking mechanisms relevant to neuronal heath and function. One of these was inspired by recent human genetics studies linking RME-8/DNAJC13 to neurological disease, including Parkinsonism and Essential Tremor. We extended our RME-8/DNAJC13 protein studies into neurons to find that that loss of RME-8/DNAJC13 in C. elegans and mouse neurons (in collaboration with Qian Cai) result in accumulation of grossly elongated autolysosomal tubules (Swords et al., 2024). In C. elegans we found that loss of RME-8 causes severe depletion of clathrin from neuronal autolysosomes, a phenotype shared with PI(3)P regulators bec-1/beclin and vps-15 (Swords et al., 2024). We concluded that RME-8/DNAC13 plays a conserved but previously unrecognized role in autophagic lysosome reformation affecting ALR tubule severing. While we continue to define how this mechanism works, our studies already provide new insight into how lysosomal recycling tubules are released, suggest that ALR feeds back to autophagic flux control, and provides a likely explanation for how RME-8 contributes to neurodegenerative disease by contributing to lysosome function/dysfunction.