KIF1A-driven entry of degradative lysosomes into the axon is developmentally regulated by the microtubule environment at the axon initial segment

KIF1A is required for dendritic and axonal localization of lysosomal vesicles in rat hippocampal neurons, and the AIS microtubule environment restricts cathepsin D-positive degradative lysosome entry in mature cells.

• Why it matters: Neurons need tightly controlled lysosome trafficking, but how spatial cues at the axon initial segment and developmental state regulate KIF1A-driven transport is not well defined.
• What they did: In immature and mature rat hippocampal neurons, the study tests KIF1A requirement for lysosomal localization and uses AIS microtubule disruption or a hereditary spastic paraplegia type 30 KIF1A variant with increased affinity for GTP-tubulin to assess entry of cathepsin D-positive vesicles.
• The result: Disrupting the AIS microtubule environment or expressing the KIF1A variant bypasses the restriction, and in human iPSC-derived neurons KIF1A depletion disrupts axonal transport, increases autophagic vesicle accumulation, and triggers axonal degeneration.

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