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Human Molecular Genetics Advance Access originally published online on April 17, 2008
Human Molecular Genetics 2008 17(15):2257-2264; doi:10.1093/hmg/ddn126
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Published by Oxford University Press 2008

Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease

Yun-Ping Wu1, Kiyomi Mizugishi1, Meryem Bektas1, Roger Sandhoff2 and Richard L. Proia1,*

1 Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1821, USA 2 Cellular and Molecular Pathology, German Cancer Research Center, INF 280 69120, Heidelberg, Germany

* To whom correspondence should be addressed at: National Institutes of Health, Building 10, Room 9D-06, 10 Center DR MSC 1821, Bethesda, MD 20892-1821, USA. Tel: +1 3014964391; Fax: +1 3014969878; Email: proia{at}nih.gov

Received February 26, 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 involved in many types of neurodegeneration, the Sphk1/S1P receptor signaling axis may be generally important during the pathogenesis of neurodegenerative diseases.


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