Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy

• Published in: Scientific reports Vol. 5; no. 1; p. 15213
• Main Authors: Moruno Manchon, Jose Felix, Uzor, Ndidi-Ese, Dabaghian, Yuri, Furr-Stimming, Erin E., Finkbeiner, Steven, Tsvetkov, Andrey S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-10-2015; Nature Publishing Group
• Subjects: 14/35; 14/63; 49/47; 631/378/340; 631/80/39/2346; Aldehyde-Lyases - antagonists & inhibitors; Aldehyde-Lyases - metabolism; Animals; Autophagy; Autophagy - drug effects; Autophagy - genetics; Biomarkers; Cell survival; Cell Survival - drug effects; Cytoplasm; Endoplasmic Reticulum - metabolism; Endosomes; Endosomes - metabolism; Enzyme Inhibitors - pharmacology; Enzymes; Gene Expression; Humanities and Social Sciences; Huntingtin; Huntington's disease; Kinases; Lysophospholipids - metabolism; multidisciplinary; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - metabolism; Neurotoxicity; Organelles; Phagocytosis; Phagosomes; Phagosomes - metabolism; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Binding; Protein Transport; Rats; Science; Signal Transduction; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine 1-phosphate; Sphingosine kinase
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep15213

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.