Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy

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
DOI: 10.1038/srep15213 Publication Date: 2015-10-19T09:46:09Z
ABSTRACT
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (51)
CITATIONS (74)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....