Lipid-mediated impairment of axonal lysosome transport contributing to autophagic stress

Abstract

Efficient degradation of autophagic vacuoles (AVs) generated at axon terminals by mature lysosomes enriched in the cell body represents an exceptional challenge that neurons face in maintaining cellular homeostasis. Here, we discuss our recent findings revealing a lipid-mediated impairment of lysosome transport to distal axons contributing to axonal AV accumulation in the neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC). Using transmission electron microscopy, we observed a striking buildup of endocytic and autophagic organelles in NPC dystrophic axons, indicating defects in the clearance of organelles destined for lysosomal degradation. We further revealed that elevated cholesterol on NPC lysosome membranes abnormally sequesters motor-adaptors of axonal lysosome delivery, resulting in impaired anterograde lysosome transport into distal axons that disrupts maturation of axonal AVs during their retrograde transport route. Together, our study demonstrates a mechanism by which altered membrane lipid composition compromises axonal lysosome trafficking and positioning and shows that lowering lysosomal lipid levels rescues lysosome transport into NPC axons, thus reducing axonal autophagic stress at early stages of NPC disease.

Keywords: Autophagy; Niemann-Pick disease type C; axonal dystrophy; axonal transport; cholesterol; kinesin; lipid; lysosomal storage disorder; lysosome; neurodegeneration.

Figure 1.

Schematic model showing lipid-mediated sequestration of motor-adaptor proteins impairs axonal lysosome delivery, contributing to autophagic stress in NPC axons. In WT neurons, the ARL8-PLEKHM2/SKIP-kinesin-1 complex is appropriately recruited to and assembled on lysosome membranes in the soma, driving lysosome transport into axons to facilitate axonal autophagosome maturation and clearance. In NPC neurons, altered membrane lipid composition on somatic lysosomes sequesters ARL8 and kinesin-1 independent of PLEKHM2/SKIP, disrupting lysosome transport to distal axons. Inefficient lysosome delivery impairs axonal autophagosome maturation, resulting in increased autophagic stress in presymptomatic NPC axons. Reducing lysosomal membrane cholesterol with HPCD treatment releases ARL8 and kinesin-1 sequestration, thus rescuing lysosome transport into axons and reducing axonal autophagosome accumulation at early stages of NPC disease