Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy

Sci Rep. 2015 Oct 19;5:15213. doi: 10.1038/srep15213.

Abstract

Autophagy is an important homeostatic mechanism that eliminates long-lived proteins, protein aggregates and damaged organelles. Its dysregulation is involved in many neurodegenerative disorders. Autophagy is therefore a promising target for blunting neurodegeneration. We searched for novel autophagic pathways in primary neurons and identified the cytosolic sphingosine-1-phosphate (S1P) pathway as a regulator of neuronal autophagy. S1P, a bioactive lipid generated by sphingosine kinase 1 (SK1) in the cytoplasm, is implicated in cell survival. We found that SK1 enhances flux through autophagy and that S1P-metabolizing enzymes decrease this flux. When autophagy is stimulated, SK1 relocalizes to endosomes/autophagosomes in neurons. Expression of a dominant-negative form of SK1 inhibits autophagosome synthesis. In a neuron model of Huntington's disease, pharmacologically inhibiting S1P-lyase protected neurons from mutant huntingtin-induced neurotoxicity. These results identify the S1P pathway as a novel regulator of neuronal autophagy and provide a new target for developing therapies for neurodegenerative disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde-Lyases / antagonists & inhibitors
  • Aldehyde-Lyases / metabolism
  • Animals
  • Autophagy* / drug effects
  • Autophagy* / genetics
  • Biomarkers
  • Cell Survival / drug effects
  • Cytoplasm
  • Endoplasmic Reticulum / metabolism
  • Endosomes / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression
  • Lysophospholipids / metabolism*
  • Neurons / metabolism*
  • Phagosomes / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Binding
  • Protein Transport
  • Rats
  • Signal Transduction*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism

Substances

  • Biomarkers
  • Enzyme Inhibitors
  • Lysophospholipids
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Aldehyde-Lyases
  • sphingosine 1-phosphate lyase (aldolase)
  • Sphingosine