bioRxiv : the preprint server for biologyAug 1, 2026

KIF1A protein is needed for waste removal inside human nerve cells

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Updated Aug 3, 2026

Abstract

KIF1A loss resulted in a significant reduction in autophagosome biogenesis and axonal autophagosome density.

Mutations in KIF1A are linked to a range of neurodevelopmental and neurodegenerative disorders.
KIF1A is essential for the proper trafficking of ATG9, which is important for forming autophagosomes.
Decreased KIF1A function led to fewer autophagosomes and lower density of these structures in neurons.
Loss of KIF1A also resulted in lysosome depletion in the axon, affecting autophagosome maturation.
Neurons with a pathogenic KIF1A variant showed notable deficits in autophagy and lysosomal trafficking.

Simplified

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.

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KIF1A protein is needed for waste removal inside human nerve cells

Abstract

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