We have determined that the sphingosine kinase/S1P receptor axis has a significant role during neurodegeneration. We used a well-established Sandhoff mouse model of neurodegeneration, which included neuronal apoptosis, inflammation and gliosis. In order to determine if S1P production was important during the neurodegenerative process we deleted the Sphk1 gene in the Sandhoff model. We found a significant improvement in life span and clinical condition of these mice compared with the control Sandhoff mice with a normal Sphk1 gene. These results indicate that Sphk1 expression may have contributed to the neurodegenerative course. Future experiments will address the mechanism of the improved course of the disease.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$485,808
Indirect Cost
City
State
Country
Zip Code
Regier, Debra S; Proia, Richard L; D'Azzo, Alessandra et al. (2016) The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy. Pediatr Endocrinol Rev 13 Suppl 1:663-73
Weth-Malsch, Daniela; Langeslag, Michiel; Beroukas, Dimitra et al. (2016) Ablation of Sphingosine 1-Phosphate Receptor Subtype 3 Impairs Hippocampal Neuron Excitability In vitro and Spatial Working Memory In vivo. Front Cell Neurosci 10:258
Spiegel, Sarah; Proia, Richard L (2016) In Memoriam: Roscoe Owen Brady (1923-2016). J Lipid Res :
Proia, Richard L; Hla, Timothy (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125:1379-87
Gupta, Sita D; Gable, Kenneth; Alexaki, Aikaterini et al. (2015) Expression of the ORMDLS, modulators of serine palmitoyltransferase, is regulated by sphingolipids in mammalian cells. J Biol Chem 290:90-8
Blaho, Victoria A; Galvani, Sylvain; Engelbrecht, Eric et al. (2015) HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523:342-6
Weth, Daniela; Benetti, Camilla; Rauch, Caroline et al. (2015) Activated platelets release sphingosine 1-phosphate and induce hypersensitivity to noxious heat stimuli in vivo. Front Neurosci 9:140
Novgorodov, Sergei A; Riley, Christopher L; Yu, Jin et al. (2014) Essential roles of neutral ceramidase and sphingosine in mitochondrial dysfunction due to traumatic brain injury. J Biol Chem 289:13142-54
Allende, Maria Laura; Proia, Richard L (2014) Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function. Glycoconj J 31:613-22
Camprubi-Robles, Maria; Mair, Norbert; Andratsch, Manfred et al. (2013) Sphingosine-1-phosphate-induced nociceptor excitation and ongoing pain behavior in mice and humans is largely mediated by S1P3 receptor. J Neurosci 33:2582-92

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