Abstract
<jats:p>Mutations in the molecular motor protein KIF1A result in a spectrum of neurodevelopmental and neurodegenerative disorders termed KIF1A-Associated Neurological Disorder (KAND). KIF1A mutations variably disrupt synaptic vesicle trafficking, but the effects of KIF1A mutations on other trafficking pathways remain unexplored. Autophagy is a conserved pathway required for neuronal homeostasis. We investigated the role of KIF1A in autophagy using gene-edited human IPSC-derived neurons. KIF1A loss inhibited the trafficking of ATG9, a transmembrane lipid scramblase necessary for autophagosome biogenesis. This deficit significantly reduced autophagosome biogenesis and the density of axonal autophagosomes. KIF1A loss also depleted lysosomes from the axon, inhibiting autophagosome maturation. In neurons gene-edited to heterozygously express a pathogenic variant linked to a Rett-like syndrome in KAND patients, we also noted significant deficits in autophagy and lysosomal trafficking. Together, these results suggest that KIF1A-mediated transport is critical to neuronal autophagy and that deficits in autophagy may contribute to pathogenesis in KAND.</jats:p>