Department of Neuroscience & Regenerative Medicine
Department of Medicine
PhD, University of Cologne, Cologne, Germany, 1990
Dr. Erhard Bieberich
Department of Neuroscience and Regenerative Medicine
Medical College of Georgia
1120 15th Street Room CA-4012
Augusta, GA 30912
The greatest challenge in molecular cell biology is to understand the translation of a molecular interaction into a biological phenotype . During embryonic development, this molecular interaction regulates stem cell migration and germ layer formation, two processes essential for shaping the human embryo and ultimately, us. In cancer, specific molecular interactions determine the formation of tumors and tumor-supporting tissue from stem cells. In our group, we study how the molecular interaction of a particular lipid (ceramide) with a cell signaling protein (protein kinase C (PKC)) regulates embryonic development, stem cell differentiation, and cancer. We apply multidisciplinary approaches ranging from molecular modeling and organic chemistry to molecular and developmental biology. Our work has shown that there is a close relationship between tumor and stem cell biology. Eventually, this knowledge will help us to better understand the coordinated development of the embryo, to improve stem cell therapy, and to fight cancer.
2000: Organic synthesis and characterization of novel ceramide analogs . We have, for the first time, synthesized novel ceramide analogs that are water-soluble
(natural ceramide is insoluble) and induce apoptosis (programmed cell death) specifically
in cancer cells.
2001/2: Discovery that in cancer as well as stem cells, expression of the atypical PKC (aPKC) inhibitor protein PAR-4 (prostate apoptosis response 4) is required to sensitize cells toward ceramide or novel ceramide analog-induced apoptosis.
2003: First description of the asymmetric distribution of PAR-4 during stem cell division. Only the PAR-4 expressing daughter cell dies by ceramide-induced apoptosis. We have proposed that this mechanism regulates the stem cell number during embryonic development.
2004: Discovery that PAR-4 and Oct-4 (pluripotency marker for stem cells) are co-expressed in tumorigenic stem cells. Incubation of stem cells with novel ceramide analogs eliminates tumor-(teratoma) forming cells and promotes neural differentiation of stem cell transplants. This treatment will significantly improve stem cell therapy.
2004/5: Novel model for the regulation of PKC-dependent cell signaling pathways by ceramide : SLIPS (sphingolipid-induced protein scaffolds). Ceramide can be good (PKC activator) or bad (PKC inhibitor) for the cell, depending on the protein complex induced by ceramide binding.
2006: Activation of atypical PKC (aPKC) by binding to ceramide. Ceramide activates aPKC and promotes NF-?B-dependent cell survival unless PAR-4 is expressed. PAR-4 binds to and inhibits ceramide-associated aPKC, downregulates NF-?B, and induces cell death. This is the first study visualizing the interaction of ceramide with a protein complex (aPKC/PAR-4).
2007 : Ceramide is critical for cell polarity. The SLIPS concept predicts that ceramide-mediated activation will also trigger factors downstream of aPKC. One of the most important processes downstream of aPKC is cell polarity. A recent study from our laboratory, for the first time, demonstrates that primitive ectoderm cells fail to establish epithelial morphology and apicobasal polarity in the absence of ceramide. Polarity and primitive ectoderm formation is restored by novel ceramide analogs. Also, first polyclonal antibody against ceramide produced in our laboratory.
2008 : Ceramide is critical for neural precursor cell migration and brain development. Since aPKC is also essential for neural precursor cell migration, we tested if ceramide
regulates aPKC in this process. Using a combination of in vitro and in vivo approaches,
the most recent study clearly shows that ceramide activates neural precursor cell
migration. Without ceramide, cortical development is severely disturbed and shows
a phenotype similar to aPKC deficiency.
2009 : Ceramide is fundamental for cell polarity and ciliogenesis. In addition to its critical role for cell migration, we found that ceramide is enriched in a pericentrosomal compartment at the base of primary cilia. Depleting cells of ceramide abolished ciliogenesis, while supplementation of ceramide-deficient cells with exogenous ceramide or ceramide analogs restored cilia formation. These results show that a ceramide-enriched compartment critically regulates cell polarity-related processes such as ciliogenesis.
2010: Good ceramide gone bad : Our model proposed in 2004 suggesting that ceramide can be good or bad depending on the cellular context is now further substantiated in three of our projects: fetal alcohol syndrome, Alzheimer's disease, and breast cancer. In these biological processes, ceramide that is useful for cell polarity and migration has gone bad and induces cell death due to the expression of the ceramide sensitizer protein PAR-4. Our studies clearly show how a particular molecular interaction (lipid-protein binding) translates into similar, but unrelated disease phenotypes. We are now testing if these phenotypes can be corrected by detoxifying ceramide, or if ceramide can be toxified to kill cancer cells.
2012-14 : Exosomes in Alzheimer’s disease. One of the roles of “bad ceramide” was found when we discovered that astrocytes secrete extracellular lipid vesicles or exosomes that can induce apoptosis. Exosome secretion was triggered by amyloid peptide, whose accumulation in plaques is one of the major causes for neurodegeneration in Alzheimer’s disease. Exosome secretion and apoptosis induction was critically dependent on activation of neutral sphingomyelinase 2 (nSMase2), an enzyme that generates ceramide from sphingomyelin, and PAR-4 attached to astrocyte-secreted exosomes. The role of ceramide/PAR-4 enriched exosomes for the progression of Alzheimer’s disease is in process. In recent studies (2014), we found that exosome reduction in vivo (by inhibition of nSMase2) leads to lower amyloid plaque load in a mouse model of Alzheimer’s disease.
2012-14 : Ceramide in ciliogenesis. Studies following up on our first description of an (apical) ceramide-enriched compartment (ACEC) at the base of cilia showed that “good ceramide” is critical for ciliogenesis in stem and neural progenitor cells. Currently, we are investigating the cell signaling pathway by which ceramide regulates cilia. Ceramide appears to inhibit deacetylation of tubulin in microtubules that form the “cytoskeleton” of cilia. Acetylation of tubulin is known to stabilize cilia and therefore, ceramide is an essential and dynamic regulator for cilium assembly and length. In addition, we found that a particular ceramide, C24:1 ceramide is a potent inducer of neural process extension, which indicates a broader function of ceramide for the regulation of the cytoskeleton.
Selected Publications (up to 15)
1. Wang, G., Silva, J., Dasgupta, S., and Bieberich, E. (2008) Long-chain ceramide is elevated in Presenilin 1 (PS1M146V) mouse brain and induces apoptosis in PS1 astrocytes. Glia, 56, 449-456.
2. Wang, G., Krishnamurthy, K., Chiang, Y.-W., Dasgupta, S., and Bieberich, E (2008) Regulation of neural progenitor cell motility by ceramide and potential implications for mouse brain development, J. Neurochem. 106, 718-733.
3. Krishnamurthy, K., Wang, G., Rokhfeld, D., and Bieberich, E. (2008) Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide. Breast Cancer Res. 10, R106.
7. Bieberich, E. (2012) Ceramide and S1P signaling in embryonic stem cell differentiation. Meth. Mol. Biol., 874;177-92.
8. Bieberich, E. (2012) It’s a lipid’s world: Bioactive lipid metabolism and signaling in neural stem cell differentiation. Neurochem. Res., 37, 1208-1229.
9. Wang, G., Dinkins, M., He, Q., Zhu, G., Poirier, C., Campbell, A., Mayer-Proschel, M., and Bieberich, E. (2012) Astrocytes secrete exosomes enriched with pro-apoptotic ceramide and prostate apoptosis response 4 (PAR-4): a potential mechanism of apoptosis induction in Alzheimer’s disease (AD). J. Biol. Chem., 287, 21384-21395.
10. He, Q., Wang, G., Dasgupta, S., and Bieberich, E. (2012) Characterization of an Apical Ceramide-Enriched Compartment regulating ciliogenesis. Mol. Biol. Cell, 23, 3156-3166.
11. Dinkins, M., Dasgupta, S., Wang, G., Zhu, G., and Bieberich, E. (2014) Exosome Reduction In Vivo Is Associated with Lower Amyloid Plaque Load in the 5XFAD Mouse Model of Alzheimer’s Disease. Neurobiol. Aging. 35,1792-800.
12. He, Q., Wang, G., Wakade, S., Dasgupta, S., Dinkins, M., Kong, JN., Spassieva,
S., and Bieberich, E. (2014) Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase
2 and ceramide. Molecular Biology of the Cell. 25, 1715-1729.