Objective:  

To advance our understanding of the process by which the mutant huntingtin (mHTT) protein contributes to neurodegeneration and translate that knowledge to potentially effective disease modifying therapies.

Background:
Huntington’s disease (HD) is a hereditary progressive neurodegenerative disease for which there is no approved disease modifying therapy. While significant progress has been made in understanding the pathophysiology of HD, the process by which mHtt causes cell death remains in question. Sphingosine and sphingosine-1-phosphate (S1P) are signaling lipids that differentially regulate cell fate, whereby sphingosine is associated with apoptosis while S1P generally promotes cell survival. A recent metabolomics analysis revealed that S1P is a disease-associated metabolite in HD, and that S1P levels are significantly downregulated in striatal neuronal progenitor HD cells. We recently demonstrated that sphingosine-1-phosphate lyase (S1PL), an enzyme that irreversibly metabolizes S1P, regulates neuronal autophagy, and identified S1PL as a possible therapeutic target, . Novartis recently reported that S1PL inhibitors may be new possible agents against multiple sclerosis. Earlier, inhibition of S1PL in models of lung injury, myopathy, rheumatoid arthritis8, and atherosclerosis has been suggested as a therapeutic strategy.

Methods:  

We use an HD model based on cultured striatal and cortical neurons, the most affected in HD, derived from embryonic rats. A novel microscopy system, an automated imaging and longitudinal analysis, enables us to track large cohorts of individual neurons over their lifetimes. We expressed S1PL in neurons, imaged them over time, and then applied statistical approaches used in clinical medicine to determine if the enzyme modulates the degradation of mHtt and affects neuronal survival.

Results:  We found that S1PL decreases flux through autophagy and inhibits the degradation of mHtt. In a neuron model of HD, pharmacologically inhibiting S1PL with THI protected neurons from mHtt-induced neurotoxicity. We plan to determine if inhibiting S1PL alleviates disease phenotypes in HD mice.

Conclusions:  These results identify S1PL as a novel therapeutic target in HD and provide a new target for developing therapies for neurodegenerative disorders.
 

References: Maceyka M, Harikumar KB, Milstien S, Spiegel S. Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol. 2012;22: 50-60.

 Pirhaji L, Milani P, Leidl M, et al. Revealing disease-associated pathways by network integration of untargeted metabolomics. Nat Methods. 2016.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/inhibiting-sphingosine-1-phosphate-lyase-as-a-possible-therapy-in-huntingtons-disease/