부산대학교 도서관

Neurons face unique challenges in maintaining cellular homeostasis in axons far removed from the cell body where lysosomes are enriched. Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterized by lipid accumulation in endolysosomes. An early pathologic hallmark of NPC is axonal dystrophy with bulbous swellings that contain accumulated organelles at presymptomatic stages prior to neuron loss in NPC mice. However, the mechanisms underlying these axonal pathologic changes remain obscure. Here, we demonstrate that organelles of the endocytic and autophagic pathways accumulate in NPC dystrophic axons. Using STED super-resolution and live-neuron imaging, we reveal that elevated cholesterol on NPC lysosome membranes in the soma leads to the sequestration of Arl8 and kinesin-1, resulting in impaired anterograde transport of mature degradative lysosomes to distal axons, contributing to axonal autophagosome accumulation. Pharmacologic reduction of lysosomal membrane cholesterol with 2-hydroxypropyl-β-cyclodextrin (HPCD) or elevated expression of Arl8b rescues lysosome transport into axons, thereby reducing axonal autophagic stress and neuron death in NPC. Collectively, these findings suggest a new pathological mechanism by which altered membrane lipid composition impairs lysosome delivery into axons of NPC neurons and provide biological insights into the translational application of HPCD in restoring axonal homeostasis at early stages of NPC disease.