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: Autophagosome; Sphingosine Kinase

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