Group: Regenerative Neurobiology group, Institute of Life Science I, Swansea University Medical School, Swansea, U.K.
Key members: Spyridon Theofilopoulos, Sotirios Ntikas, Joanna Bartlett
Contact: Spyridon Theofilopoulos, firstname.lastname@example.org
Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms include tremor, rigidity and hypokinesia and generally appear slowly over time. The main pathological finding is a progressive degeneration of substantia nigra neurons leading to severe loss of striatal dopamine innervation. Unfortunately at present there is no cure.
Specific cholesterol metabolites function as ligands of nuclear receptors, including Liver X receptors (LXRs), which are ligand-dependent transcription factors. LXRs (Lxrα/NR1H3 and Lxrβ/NR1H2) are well known regulators of lipid metabolism and inflammation, but have also recently emerged as key factors for neurogenesis and maintenance of neuronal survival. I and others have previously reported, by in vitro and in vivo experiments, that Lxrs control different aspects of midbrain dopamine (mDA) neuron development (Sacchetti et al., 2009, Cell Stem Cell) and that endogenous brain LXR ligands are an entirely new family of highly selective and potent regulators of midbrain neurogenesis and/or survival (Theofilopoulos et al., 2013, Nature Chemical Biology; Theofilopoulos*, Griffiths* et al., 2014, J. Clinical Investigation).
Our current objectives are:
(1) Identify the function and mechanism of action of cholesterol metabolites up- or down-regulated in PD patients by using Mass Spectrometry and several mouse in vitro techniques [collaborative work with William J. Griffiths and Yuqin Wang from the School of Medicine, Swansea University, as well as with Ernest Arenas from the Division of Molecular Neurobiology, Karolinska Institute]
(2) Utilise LXR ligands to improve protocols for the in vitro DA differentiation of mouse and human ES cell lines as well as several other cell types
(3) Examine whether newly identified neuroprotective LXR ligands can prevent or rescue phenotypic features of PD in rodent models of PD in vivo [collaborative work with Mariah Lelos from the School of Biosciences, Cardiff University]
Key papers related to ENOR:
24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo. Theofilopoulos, S., Abreu de Oliveira, W.A., Yang, S., Yutuc, E., Saeed, A., Abdel-Khalik, J., Ullgren, A., Cedazo-Minguez, A., Björkhem, I., Wang, Y., Griffiths, W.J., Arenas, E. (2019). J Biol Chem. 294(11), 4169-4176.
Liver X receptors and cholesterol metabolism: role in ventral midbrain development and neurodegeneration. Theofilopoulos, S. & Arenas, E. (2015). F1000Prime Reports 7:37.
Cholestenoic acids regulate motor neuron survival via liver X receptors. Theofilopoulos, S., Griffiths, W., Crick, P., Yang, S., Meljon, A., Ogundare, M., Kitambi, S., Lockhart, A., Tuschl, K., Clayton, P., Morris, A., Martinez, A., Reddy, M., Martinuzzi, A., Bassi, M., Honda, A., Mizuochi, T., Kimura, A., Nittono, H., De Michele, G., Carbone, R., Criscuolo, C., Yau, JL., Seckl, JR., Schüle, R., Schöls, L., Sailer, AW., Kuhle, J., Fraidakis, MJ., Gustafsson, JÅ., Steffensen, KR., Björkhem, I., Ernfors, P., Sjövall, J., Arenas, E. & Wang, Y. (2014). Journal of Clinical Investigation 124(11), 4829-4842.
Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis. Theofilopoulos, S., Wang, Y., Kitambi, S., Sacchetti, P., Sousa, K., Bodin, K., Kirk, J., Saltó, C., Gustafsson, M., Toledo, E., Karu, K., Gustafsson, J., Steffensen, K., Ernfors, P., Sjövall, J., Griffiths, W. & Arenas, E. (2013). Nature Chemical Biology 9(2), 126-133.
Liver X Receptors and Oxysterols Promote Ventral Midbrain Neurogenesis In Vivo and in Human Embryonic Stem Cells. Sacchetti, P., Sousa, K., Hall, A., Liste, I., Steffensen, K., Theofilopoulos, S., Parish, C., Hazenberg, C., Richter, L., Hovatta, O., Gustafsson, J. & Arenas, E. (2009). Cell Stem Cell 5(4), 409-419.