Lipid-mediated motor-adaptor sequestration impairs axonal lysosome delivery leading to autophagic stress and dystrophy in Niemann-Pick type C.

Abstract

Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterized by lipid accumulation in endolysosomes. An early pathologic hallmark is axonal dystrophy occurring at presymptomatic stages in NPC mice. However, the mechanisms underlying this pathologic change remain obscure. Here, we demonstrate that endocytic-autophagic organelles accumulate in NPC dystrophic axons. Using super-resolution and live-neuron imaging, we reveal that elevated cholesterol on NPC lysosome membranes sequesters kinesin-1 and Arl8 independent of SKIP and Arl8-GTPase activity, resulting in impaired lysosome transport into axons, contributing to axonal autophagosome accumulation. Pharmacologic reduction of lysosomal membrane cholesterol with 2-hydroxypropyl-β-cyclodextrin (HPCD) or elevated Arl8b expression rescues lysosome transport, thereby reducing axonal autophagic stress and neuron death in NPC. These findings demonstrate a pathological mechanism by which altered membrane lipid composition impairs lysosome delivery into axons and provide biological insights into the translational application of HPCD in restoring axonal homeostasis at early stages of NPC disease.

• Authors: Joseph C Roney, Sunan Li, Tamar Farfel-Becker, Ning Huang, Tao Sun, Yuxiang Xie, Xiu-Tang Cheng, Mei-Yao Lin, Frances M Platt, Zu-Hang Sheng
• Journal: Developmental cell (Dev Cell) Vol. 56 Issue 10 Pg. 1452-1468.e8 (05 17 2021) ISSN: 1878-1551 [Electronic] United States
• PMID: 33878344 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Lipids
• Niemann-Pick C1 Protein
• Npc1 protein, mouse
• Cholesterol
• GTP Phosphohydrolases
• Kinesins

Topics

• Animals
• Autophagosomes (metabolism, ultrastructure)
• Autophagy
• Axons (metabolism)
• Biological Transport
• Cell Death
• Cholesterol (metabolism)
• Cytoplasmic Vesicles (metabolism, ultrastructure)
• GTP Phosphohydrolases (metabolism)
• Intracellular Membranes (metabolism)
• Kinesins (metabolism)
• Lipids (chemistry)
• Lysosomes (metabolism)
• Mice, Inbred BALB C
• Muscular Dystrophies (complications, pathology)
• Niemann-Pick C1 Protein (deficiency, metabolism)
• Niemann-Pick Disease, Type C (complications, pathology)
• Stress, Physiological