ArticleHuman molecular genetics2017
Inhibiting sphingosine kinase 2 mitigates mutant Huntingtin-induced neurodegeneration in neuron models of Huntington disease.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.Molecular psychiatry · 2026Article
- The physiological and pathological effects of sphingolipid metabolism and signaling in the central nervous system.Brain pathology (Zurich, Switzerland) · 2026Review
- Seasonal and comparative evidence of adaptive gene expression in mammalian brain size plasticity.eLife · 2025Article
- Serum metabolome profiling in patients with mild cognitive impairment reveals sex differences in lipid metabolism.bioRxiv : the preprint server for biology · 2024Article
- Sphingosine kinase 2 regulates protein ubiquitination networks in neurons.Molecular and cellular neurosciences · 2024Article
- Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex-dependent manner.Aging cell · 2023Article
- The Tardigrade damage suppressor protein Dsup promotes DNA damage in neurons.Molecular and cellular neurosciences · 2023Article
- Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration.International journal of molecular sciences · 2023Review
- Treatment with THI, an inhibitor of sphingosine-1-phosphate lyase, modulates glycosphingolipid metabolism and results therapeutically effective in experimental models of Huntington's disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Loss of sphingosine kinase 2 protects against cisplatin-induced kidney injury.American journal of physiology. Renal physiology · 2022Article
- Article
- The Functional Role of Sphingosine Kinase 2.Frontiers in molecular biosciences · 2021Review
- Sphingosine kinase 2 inhibitor ABC294640 suppresses neuronal excitability and inhibits multiple endogenously and exogenously expressed voltage-gated ion channels in cultured cells.Channels (Austin, Tex.) · 2020Article
- Article
- The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration.Molecular neurobiology · 2019Review
- Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases.Frontiers in pharmacology · 2019Review
- Stimulation of Sphingosine Kinase 1 (SPHK1) Is Beneficial in a Huntington's Disease Pre-clinical Model.Frontiers in molecular neuroscience · 2019Article
- Nuclear lipid mediators: Role of nuclear sphingolipids and sphingosine-1-phosphate signaling in epigenetic regulation of inflammation and gene expression.Journal of cellular biochemistry · 2018Review
- Sphingosine kinase 1-associated autophagy differs between neurons and astrocytes.Cell death & disease · 2018Article
- Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders.Frontiers in neuroscience · 2018Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
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