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 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.
Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX 77030, USA.
Jose F
JF
Moruno-Manchon
Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Ndidi-Ese
NE
Uzor
Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX 77030, USA.
Maria P
MP
Blasco-Conesa
The University of Texas Medical Training Program, Houston, TX 77030, USA.
Sishira
S
Mannuru
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Nagireddy
N
Putluri
Department of Neurology, The University of Texas McGovern Medical School, Houston, TX 77030, USA.
Erin E
EE
Furr-Stimming
Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Andrey S
AS
Tsvetkov
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099157:Sphingosine Kinase
D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D000071058:Huntingtin Protein; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C000603447:sphingosine kinase 2, mouse