Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy

• DOI: 10.1038/srep15213
• Publication Date: 2015-10-19T09:46:09Z
• Authors: Jose Felix Moruno...; Ndidi-Ese Uzor; Yuri Dabaghian; Erin E. Furr-Stim...; Steven Finkbeiner; Andrey S. Tsvetkov
• Keywords: 0301 basic medicine; Cytoplasm; Cell Survival; Gene Expression; Endosomes; Neurodegenerative; Endoplasmic Reticulum; Article; Medicinal and Biomolecular Chemistry; 03 medical and health sciences; Rare Diseases; Sphingosine; Phagosomes; Autophagy; 2.1 Biological and endogenous factors; Animals; Aetiology; Enzyme Inhibitors; Aldehyde-Lyases; Neurons; 2. Zero hunger; 0303 health sciences; Neurosciences; Biological Sciences; Brain Disorders; Rats; 3. Good health; Phosphotransferases (Alcohol Group Acceptor); Protein Transport; Chemical Sciences; Neurological; Biochemistry and Cell Biology; Lysophospholipids; Biomarkers; Biotechnology; Protein Binding; Signal Transduction

AbstractAutophagy 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.