Ultrastructural studies reveal a new role for JIP3/MAPK8IP3 in endo-lysosomal maturation within the neuronal cell body.

In recent years, substantial heterogeneity in lysosomes, in terms of their composition, function, and positioning, has come to be recognized. Despite this, there are gaps in knowledge of our understanding of the molecular basis of lysosome heterogeneity, especially in neurons. To this end, we used electron microscopy to define endolysosomal organelles of human iPSC-derived neurons at the ultrastructural level. Through this, we identify endolysosomal maturation defects within neuronal cell bodies of iNeurons lacking JNK-Interacting Protein 3 (JIP3), a lysosome adaptor previously known to primarily regulate axonal lysosome movement. Loss of JIP3 results in an expansion of immature lysosomes within neuronal soma, along with a concomitant decrease in mature lysosomes. JIP3 loss also leads to delayed trafficking of endocytic cargo through these compartments, implicating JIP3 in the regulation of endolysosomal maturation within neuronal cell bodies. Our studies highlight the utility of electron microscopy in understanding neuronal lysosomal heterogeneity. Additionally, given recent links between JIP3 and a neurodevelopmental disorder, our findings here could provide new insight into mechanisms underlying neurodevelopmental pathology.