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

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.

Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress

“…Furthermore, ongoing clinical trials with SK2 inhibitors have not reported any drug-related toxicities in humans [ 11 ], including neurotoxicity which is a common side-effect of bortezomib [ 49 ]. Indeed, in some contexts SK2 inhibition appears neuroprotective [ 50 ]. Thus, combining SK2 inhibitors with bortezomib appears feasible in humans.…”

The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration

“…SPHK2 has been found to participate in repressor complexes with histone deacetylases (HDAC1 and 2), while S1P can bind both HDAC proteins and inhibit their deacetylase activity [ 59 ]. These varied mechanisms of nuclear signaling appear to be important for inflammaging and neurodegenerative conditions (Alzheimer’s disease (AD)), along with the above mentioned sphingolipid-mediated modulation of transcription factors [ 49 , 60 , 61 ].…”

Sphingosine kinase 2 activates autophagy and protects neurons against ischemic injury through interaction with Bcl-2 via its putative BH3 domain

“…In neurons, SPK2 could be expressed in the cytoplasm, mitochondria and nucleus under physiological or pathological conditions. 41 , 42 , 43 , 44 Our previous finding showed that preconditioning mainly upregulates endogenous SPK2 in the cytoplasm. On the other hand, apoptosis-stimulating protein of p53-2 (ASPP2) could bind to Bcl-2 in the nucleus to prevent its translocation to the cytoplasm, thus contributing to Beclin-1-initiated autophagy.…”

“… 58 , 60 , 63 , 64 , 65 In neurons, SPK2 can be expressed in the cytoplasm, mitochondria and nucleus under physiological or pathological conditions. 41 , 42 , 43 , 44 Recent study suggest that overexpressed SPK2 in nucleus is neurotoxic and promotes DNA double-strand breaks in cultured primary neurons. 44 However, our data showed that SPK2 was overexpressed in both the cytoplasm and nuclei of the SPK2 overexpressed neurons and HT22 cells.…”

“… 41 , 42 , 43 , 44 Recent study suggest that overexpressed SPK2 in nucleus is neurotoxic and promotes DNA double-strand breaks in cultured primary neurons. 44 However, our data showed that SPK2 was overexpressed in both the cytoplasm and nuclei of the SPK2 overexpressed neurons and HT22 cells. On the other hand, Bcl-2 was mainly expressed in the cytoplasm of both LV-SPK2-HT22 cells and SPK2-overexpressing neurons.…”