Sphingolipid Biology of Neurodegeneration

Proia, Richard

Abstract

This past year we have attempted to determine if 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 #: 1ZIADK056016-03
• Application #: 7967619
• Support Year: 3
• Fiscal Year: 2009
• Total Cost: $302,534

Institution

• Name: National Institute of Diabetes and Digestive and Kidney Diseases

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