title: Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy.
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.
authors.affiliation: Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, TX 77030.
authors.forename: Jose Felix
authors.initials: JF
authors.lastname: Moruno Manchon
authors.affiliation: Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, TX 77030.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030.
authors.forename: Ndidi-Ese
authors.initials: NE
authors.lastname: Uzor
authors.affiliation: The Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030.|Department of Computational and Applied Mathematics, Rice University, Houston, TX 77005.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Dabaghian
authors.affiliation: Department of Neurology, University of Texas Medical School, Houston, TX 77030.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Furr-Stimming
authors.affiliation: Gladstone Institute of Neurological Disease and the Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA 94158.|Departments of Neurology and Physiology, University of California, San Francisco, CA 94143.
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.affiliation: Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, TX 77030.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Tsvetkov
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D008246:Lysophospholipids / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000446:Aldehyde-Lyases; D015415:Biomarkers; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C022649:sphingosine 1-phosphate lyase (aldolase)