Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy


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.

Journal article

Manchon, Jose Felix Moruno, Uzor, Ndidi-Ese, Dabaghian, Yuri, et al.. "Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy." Scientific Reports, 5, (2015) Springer Nature:

Has part(s)
Forms part of
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the articleメs Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.ᅠ
Citable link to this page