Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIADK056016-07
Application #
8741514
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$599,767
Indirect Cost

  Institution

Name
National Institute of Diabetes and Digestive and Kidney Diseases
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Allende, Maria L; Cook, Emily K; Larman, Bridget C et al. (2018) Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation. J Lipid Res 59:550-563
Spiegel, Sarah; Proia, Richard L (2016) In Memoriam: Roscoe Owen Brady (1923-2016). J Lipid Res :
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
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
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
Allende, Maria Laura; Proia, Richard L (2014) Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function. Glycoconj J 31:613-22
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

Showing the most recent 10 out of 16 publications