Human Molecular Genetics Advance Access published online on April 17, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn126
Published by Oxford University Press 2008
Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease
1 Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 2 Cellular and Molecular Pathology, German Cancer Research Center, INF 280, 69120 Heidelberg, Germany
To whom correspondence should be addressed: Dr. Richard L. Proia Building 10, Room 9D-06 National Institutes of Health 10 Center DR MSC 1821 Bethesda, MD 20892-1821 Phone: 301-496-4391 Fax: 301-496-9878 E-mail: proia{at}nih.gov
Received February 26, 2008; Revised April 11, 2008; Accepted April 11, 2008
Sphingosine-1-phosphate (S1P) is a lipid signaling molecule produced by sphingosine kinase in response to a wide number of stimuli. By acting through a family of widely expressed G protein-coupled receptors, S1P regulates diverse physiological processes. Here we examined the role of S1P signaling in neurodegeneration using a mouse model of Sandhoff disease, a prototypical neuronopathic lysosomal storage disorder. When sphingosine kinase 1 (Sphk1) was deleted in Sandhoff disease mice, a milder disease course occurred, with decreased proliferation of glial cells and less-pronounced astrogliosis. A similar result of milder disease course and reduced astroglial proliferation was obtained by deletion of the gene for the S1P3 receptor, a G protein-coupled receptor enriched in astrocytes. Our studies demonstrate a functional role of S1P synthesis and receptor expression in astrocyte proliferation leading to astrogliosis during the terminal stages of neurodegeneration in Sandhoff disease mice. Because astrocyte responses are widely involved in many types of neurodegeneration, the Sphk1/S1P receptor signaling axis may be generally important during the pathogenesis of neurodegenerative diseases.