Neuronal polarity: Essential role of protein–lipid complexes in axonal sorting

TLDR

HA and Thy‑1 are efficiently targeted to the axonal surface of polarized hippocampal neurons. Neurons sort axonal proteins such as HA and Thy‑1 via protein–lipid raft formation, and loss of cholesterol or sphingolipids disrupts their raft association and causes missorting, suggesting a role for rafts in axonal membrane sorting and in Niemann–Pick disease deficits.

Abstract

The viral glycoprotein hemagglutinin (HA) and the endogenous glycosylphosphatidylinositol-anchored protein Thy-1 are efficiently targeted to the axonal surface of fully polarized hippocampal neurons in culture. Here we have shown that in these cells HA and Thy-1 interact with sphingolipid–cholesterol rafts and are included in detergent-insoluble glycolipid-enriched complexes. Axonal HA and Thy-1, but not two dendritic membrane proteins, resisted extraction to detergents at 4°C. Both HA and Thy-1 became detergent-soluble in neurons with reduced levels of cholesterol or sphingolipids. Missorting of the axonal Thy-1 but not of a dendritic membrane protein occurred in sphingolipid-deprived cells. These results indicate that neurons sort a subset of axolemmal proteins by a mechanism that requires the formation of protein–lipid rafts. The involvement of rafts in axonal membrane sorting may explain the neurological deficits observed in patients with certain types of Niemann–Pick disease.