- (859) 323-9443
- 800 Rose St, Medical Science Building, Rm: MS 517A
M.S. in Biology/Biotechnology, University of Plovdiv “Paisii Hilendarski”, Plovdiv, Bulgaria, 1984 – 1989
Ph.D. in Molecular Biology, University of Groningen, Groningen, The Netherlands, 1998 – 2003
Postdoctoral Fellow, Department of Medicine, Medical University of South Carolina, Charleston, SC, 2003 – 2007
I. Role of a class of neurotoxic sphingolipids, the deoxysphingolipids, in taxane-induced peripheral neuropathy.
Taxanes are a class of widely-used chemotherapy drugs; however, more than 50% of patients can experience peripheral neuropathy as a side effect, resulting in dose reduction or treatment termination. The molecular mechanism of peripheral neuropathy is not understood, and there are currently no prevention or treatment strategies available. In a pilot study with breast cancer patients receiving standard paclitaxel chemotherapy, we tested whether a class of neurotoxic lipids, deoxysphingolipids, were involved in the development of peripheral neuropathy. Deoxysphingolipids are produced when the first enzyme of the sphingolipid biosynthetic pathway, serine palmitoyltransferase, utilizes L-alanine instead of L-serine as its amino acid substrate Deoxysphingolipids were previously shown to be elevated in the plasma of those with hereditary sensory and autonomic neuropathy type I. Importantly, they have additionally been shown to be neurotoxic in vitro by us and others to and in human when the deoxysphingolipid, deoxysphinganine (ES-285), was tested as an anticancer drug. Indeed, ES-285 phase I clinical trials were terminated because patients developed severe, and in some cases fatal, neuropathy. Our study with breast cancer patients receiving standard paclitaxel chemotherapy revealed that the incidence and severity of neuropathy was associated with plasma deoxysphingolipid levels. Currently, we are investigating the molecular mechanisms of deoxysphingolipid neurotoxicity in vitro and in mouse models of taxane-induced peripheral neuropathy. Our goal is to develop strategies to address deoxysphingolipid neurotoxicity.
II. Role of de novo ceramide synthesis in neuronal homeostasis.
In mammals, ceramide biosynthesis is catalyzed by six isoforms of ceramide synthase (CerS). Each CerS isoform has a preference for a different set of CoA-activated fatty acids according to the length of their acyl chain. A sphingoid base, together with a CoA-activated fatty acid, are the two substrates for CerS enzymes.
Data from our two unique mouse models provides compelling evidence that deficiency in ceramide biosynthesis can cause neurodegeneration. Our first mouse model is based on a point mutation in the CerS1 isoform, resulting in its catalytic inactivation, the elevation of its sphingoid base substrates, the reduction of its product (18 carbon chain ceramide), and neurodegeneration. CerS1 is the main neuronal ceramide synthase isoform. The second mouse model is based on ectopic expression in the CerS1-deficient neurons of a different ceramide synthase isoform, CerS2. In this model, the CerS2 expression reduces the levels of sphingoid bases in the brain to wild type levels while rescuing the neurodegeneration phenotype. Of note, CerS1 and CerS2 isoforms share the same sphingoid base substrates, but use different fatty acid acyl-CoAs, which produces ceramides with different fatty acyl moieties.
Using these two unique mouse models, we are investigating whether high sphingoid base levels in the brain can impair the homeostasis of membrane organelles, causing neurodegeneration. Our project aims at providing important insights for understanding the pathophysiological roles of sphingolipid metabolites, such as sphingoid bases in the nervous system. It is our goal to then use this knowledge for developing sphingolipid metabolism-based strategies to reduce neurodegeneration.
- Kong, J.N.;Zhu, Z.;Itokazu, Y.;Wang, G.;Dinkins, M.B.;Zhong, L.;Lin, H.P.;Elsherbini, A.;Leanhart, S.;Jiang, X.;Qin, H.;Zhi, W.;Spassieva, S.D.;Bieberich, E. "Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes." Journal of lipid research (2018): [PubMed Link] | [ Full text ]
- Wang, G.;Spassieva, S.D.;Bieberich, E. "Ceramide and S1P Signaling in Embryonic Stem Cell Differentiation." Methods in molecular biology (Clifton, N.J.) 1697, (2018): 153-171. [PubMed Link] | [ Full text ]
- Hammad, S.M.;Baker, N.L.;El Abiad, J.M.;Spassieva, S.D.;Pierce, J.S.;Rembiesa, B.;Bielawski, J.;Lopes-Virella, M.F.;Klein, R.L.;DCCT/EDIC Group of, I. "Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study." Neuromolecular medicine 19, 1 (2017): 46-56. [PubMed Link] | [ Full text ]
- Spassieva, S.;Bieberich, E. "Lysosphingolipids and sphingolipidoses: Psychosine in Krabbe's disease." Journal of neuroscience research 94, 11 (2016): 974-81. [PubMed Link] | [ Full text ]
- Spassieva, S.D.;Ji, X.;Liu, Y.;Gable, K.;Bielawski, J.;Dunn, T.M.;Bieberich, E.;Zhao, L. "Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency." Proceedings of the National Academy of Sciences of the United States of America 113, 21 (2016): 5928-33. [PubMed Link] | [ Full text ]
- Zhao, L.;Spassieva, S.;Gable, K.;Gupta, S.D.;Shi, L.Y.;Wang, J.;Bielawski, J.;Hicks, W.L.;Krebs, M.P.;Naggert, J.;Hannun, Y.A.;Dunn, T.M.;Nishina, P.M. "Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration." Proceedings of the National Academy of Sciences of the United States of America 112, 42 (2015): 12962-7. [PubMed Link] | [ Full text ]
- Kong, J.N.;He, Q.;Wang, G.;Dasgupta, S.;Dinkins, M.B.;Zhu, G.;Kim, A.;Spassieva, S.;Bieberich, E. "Guggulsterone and bexarotene induce secretion of exosome-associated breast cancer resistance protein and reduce doxorubicin resistance in MDA-MB-231 cells." International journal of cancer 137, 7 (2015): 1610-20. [PubMed Link] | [ Full text ]
- Kramer, R.;Bielawski, J.;Kistner-Griffin, E.;Othman, A.;Alecu, I.;Ernst, D.;Kornhauser, D.;Hornemann, T.;Spassieva, S. "Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29, 11 (2015): 4461-72. [PubMed Link] | [ Full text ]
- Kong, J.N.;Hardin, K.;Dinkins, M.;Wang, G.;He, Q.;Mujadzic, T.;Zhu, G.;Bielawski, J.;Spassieva, S.;Bieberich, E. "Regulation of Chlamydomonas flagella and ependymal cell motile cilia by ceramide-mediated translocation of GSK3." Molecular biology of the cell 26, 24 (2015): 4451-65. [PubMed Link] | [ Full text ]
- He, Q.;Wang, G.;Wakade, S.;Dasgupta, S.;Dinkins, M.;Kong, J.N.;Spassieva, S.D.;Bieberich, E. "Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide." Molecular biology of the cell 25, 11 (2014): 1715-29. [PubMed Link] | [ Full text ]
- Spassieva, S.D.;Rahmaniyan, M.;Bielawski, J.;Clarke, C.J.;Kraveka, J.M.;Obeid, L.M. "Cell density-dependent reduction of dihydroceramide desaturase activity in neuroblastoma cells." Journal of lipid research 53, 5 (2012): 918-28. [PubMed Link] | [ Full text ]
- Lee, A.J.;Roylance, R.;Sander, J.;Gorman, P.;Endesfelder, D.;Kschischo, M.;Jones, N.P.;East, P.;Nicke, B.;Spassieva, S.;Obeid, L.M.;Birkbak, N.J.;Szallasi, Z.;McKnight, N.C.;Rowan, A.J.;Speirs, V.;Hanby, A.M.;Downward, J.;Tooze, S.A.;Swanton, C. "CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction." The Journal of pathology 226, 3 (2012): 482-94. [PubMed Link] | [ Full text ]
- Spassieva, S.;Bieberich, E. "The gut-to-breast connection - interdependence of sterols and sphingolipids in multidrug resistance and breast cancer therapy." Anti-cancer agents in medicinal chemistry 11, 9 (2011): 882-90. [PubMed Link] | [ Full text ]
- Zhao, L.;Spassieva, S.D.;Jucius, T.J.;Shultz, L.D.;Shick, H.E.;Macklin, W.B.;Hannun, Y.A.;Obeid, L.M.;Ackerman, S.L. "A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation." PLoS genetics 7, 5 (2011): e1002063. [PubMed Link] | [ Full text ]
- Mullen, T.D.;Spassieva, S.;Jenkins, R.W.;Kitatani, K.;Bielawski, J.;Hannun, Y.A.;Obeid, L.M. "Selective knockdown of ceramide synthases reveals complex interregulation of sphingolipid metabolism." Journal of lipid research 52, 1 (2011): 68-77. [PubMed Link] | [ Full text ]
- Spassieva, S.D.;Mullen, T.D.;Townsend, D.M.;Obeid, L.M. "Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response." The Biochemical journal 424, 2 (2009): 273-83. [PubMed Link] | [ Full text ]
- Spassieva, S.;Bielawski, J.;Anelli, V.;Obeid, L.M. "Combination of C(17) sphingoid base homologues and mass spectrometry analysis as a new approach to study sphingolipid metabolism." Methods in enzymology 434, (2007): 233-41. [PubMed Link] | [ Full text ]
- Spassieva, S.;Seo, J.G.;Jiang, J.C.;Bielawski, J.;Alvarez-Vasquez, F.;Jazwinski, S.M.;Hannun, Y.A.;Obeid, L.M. "Necessary role for the Lag1p motif in (dihydro)ceramide synthase activity." The Journal of biological chemistry 281, 45 (2006): 33931-8. [PubMed Link] | [ Full text ]
- Koybasi, S.;Senkal, C.E.;Sundararaj, K.;Spassieva, S.;Bielawski, J.;Osta, W.;Day, T.A.;Jiang, J.C.;Jazwinski, S.M.;Hannun, Y.A.;Obeid, L.M.;Ogretmen, B. "Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas." The Journal of biological chemistry 279, 43 (2004): 44311-9. [PubMed Link] | [ Full text ]
- Sims, K.J.;Spassieva, S.D.;Voit, E.O.;Obeid, L.M. "Yeast sphingolipid metabolism: clues and connections." Biochemistry and cell biology = Biochimie et biologie cellulaire 82, 1 (2004): 45-61. [PubMed Link] | [ Full text ]
- Spassieva, S.D.;Markham, J.E.;Hille, J. "The plant disease resistance gene Asc-1 prevents disruption of sphingolipid metabolism during AAL-toxin-induced programmed cell death." The Plant journal : for cell and molecular biology 32, 4 (2002): 561-72. [PubMed Link] | [ Full text ]