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
AUTHORS (6)
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.
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