Inhibiting sphingosine kinase 2 mitigates mutant Huntingtin-induced neurodegeneration in neuron models of Huntington disease

Huntington disease (HD) is the most common inherited neurodegenerative disorder. It has no cure. The protein huntingtin causes HD, and mutations to it confer toxic functions to the protein that lead to neurodegeneration. Thus, identifying modifiers of mutant huntingtin-mediated neurotoxicity might b...

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Bibliographic Details
Published in:	Human molecular genetics Vol. 26; no. 7; pp. 1305 - 1317
Main Authors:	Moruno-Manchon, Jose F, Uzor, Ndidi-Ese, Blasco-Conesa, Maria P, Mannuru, Sishira, Putluri, Nagireddy, Furr-Stimming, Erin E, Tsvetkov, Andrey S
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 01-04-2017
Subjects:	Animals Cell Nucleus - genetics Cell Nucleus - metabolism Disease Models, Animal Gene Expression Regulation Histone Deacetylase 1 - antagonists & inhibitors Histone Deacetylase 2 - antagonists & inhibitors Humans Huntingtin Protein - genetics Huntington Disease - genetics Huntington Disease - metabolism Huntington Disease - pathology Lysophospholipids - metabolism Mice Neurons - metabolism Neurons - pathology Phosphorylation Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors Phosphotransferases (Alcohol Group Acceptor) - genetics Sphingosine - analogs & derivatives Sphingosine - metabolism
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Summary:	Huntington disease (HD) is the most common inherited neurodegenerative disorder. It has no cure. The protein huntingtin causes HD, and mutations to it confer toxic functions to the protein that lead to neurodegeneration. Thus, identifying modifiers of mutant huntingtin-mediated neurotoxicity might be a therapeutic strategy for HD. Sphingosine kinases 1 (SK1) and 2 (SK2) synthesize sphingosine-1-phosphate (S1P), a bioactive lipid messenger critically involved in many vital cellular processes, such as cell survival. In the nucleus, SK2 binds to and inhibits histone deacetylases 1 and 2 (HDAC1/2). Inhibiting both HDACs has been suggested as a potential therapy in HD. Here, we found that SK2 is nuclear in primary neurons and, unexpectedly, overexpressed SK2 is neurotoxic in a dose-dependent manner. SK2 promotes DNA double-strand breaks in cultured primary neurons. We also found that SK2 is hyperphosphorylated in the brain samples from a model of HD, the BACHD mice. These data suggest that the SK2 pathway may be a part of a pathogenic pathway in HD. ABC294640, an inhibitor of SK2, reduces DNA damage in neurons and increases survival in two neuron models of HD. Our results identify a novel regulator of mutant huntingtin-mediated neurotoxicity and provide a new target for developing therapies for HD.
ISSN:	0964-6906 1460-2083
DOI:	10.1093/hmg/ddx046