The role of sphingolipids in health and disease
The cell surface is decorated with a diverse array of proteins and lipids that play essential roles in cell contact and signalling. An important class of lipids enriched at the cell surface are glycosphingolipids (GSLs). Imbalances in GSL levels underlie a range of severe disorders from neurodegeneration to cancer. My lab investigates the molecular mechanisms by which altered sphingolipid metabolism results in devastating neurological disease. Our work explores similarities between rare genetic neuropathologies and common neurodegenerative diseases, laying the scientific foundations for future therapies.
Strategic CIMR themes: Membrane Trafficking, Rare Genetic Disease, Neurological Disease
Funding: Wellcome Trust
Research Group Members: Shannon McKie, Alex Nicholson, Emily Smith, Holly Monkhouse and Jack Welland
Research
The role of sphingolipids in health and disease
Imbalances in glycosphingolipid (GSL) homeostasis cause a range of early-onset diseases often involving rapid, fatal neurodegeneration and are implicated in later-onset diseases including cancer and diabetes. While the importance of these lipids is highlighted by the catastrophic diseases caused by GSL imbalances, the molecular details of how they contribute to cellular phenotypes remains poorly understood. To study this we use a wide range of experimental techniques including genetic modification of iPSCs to generate cell-based models of neuronal disease, quantitative proteomics and high-resolution molecular structures.
The role of GSLs in neurodegenerative disease
Several monogenic diseases affecting enzymes in the GSL metabolic pathway result in severe, early-onset neurodegenerative diseases. The lysosomal enzyme galactosylceramidase (GALC) degrades the major lipid component of the myelin sheath, galactosylceramide (GalCer), to ceramide and defects in GALC cause the severe neurodegenerative disorder Krabbe disease. Using a combination of biochemical and cellular approaches we have identified specific molecular mechanisms driving disease pathogenesis in GALC variants, highlighting therapeutic opportunities and providing insights into fundamental lipid-processing complexes.
The role of GSLs in immune presentation
Our work on GALC identified the mechanism by which GSLs are presented to lysosomal hydroalses. This mechanism involves the lipid-binding saposin proteins. Interestingly, saposins also load lipids onto the antigen-presenting molecules CD1 for immune surveillance. Our ongoing work is addressing how saposins transfer GSLs into the lipid-binding groove of CD1.
Publications
1. McKie, S.J., Nicholson, A.S., Smith, E., Fawke, S., Caroe, E., Williamson, J.C., Butt, B.G., Kolářová, D., Peterka, O., Holčapek, M., Lehner, P.J., Graham, S.C. and Deane, J.E. Altered plasma membrane abundance of the sulfatide-binding protein NF155 links glycosphingolipid imbalances to demyelination. Proc. Natl Acad. Sci. U.S.A. In press. (2023).
2. Hay, I.M., Shamin, M., Caroe, E.R., Mohammed, A.S.A., Svergun, D.I., Jeffries, C.M., Graham, S.C. Sharpe, H.J. and Deane, J.E. Determinants of receptor tyrosine phosphatase homophilic adhesion: structural comparison of PTPRK and PTPRM extracellular domains. J. Biol. Chem. 299:102750 (2023).
3. Hay, I.M., Mulholland, K.E., Lai, T., Graham, S.C., Sharpe, H.J. and Deane, J.E. Molecular mechanism of Afadin substrate recruitment to the receptor phosphatase PTPRK via its pseudophosphatase domain. eLife 11: e79855. (2022).
4. Shamin, M., Spratley, S.J., Graham, S.C. and Deane, J.E. A tetrameric assembly of saposin A: increasing structural diversity in lipid transfer proteins. Contact 4:1-11. (2021).
5. Viuff, A.H., Salamone, S., McLoughlin, J., Deane, J.E. and Jensen, H.H. The bicyclic form of galacto-noeurostegine is a potent inhibitor of β-galactocerebrosidase” ACS Med. Chem. Lett. 12: 56-59. (2021).
6. Hay, I.M., Fearnley, G.W., Rios, P., Köhn, M., Sharpe, H.J. and Deane, J.E. The receptor PTPRU is a redox sensitive pseudophosphatase. Nat. Comms 11:3219. (2020)
7. Shamin, M., Benedyk, T.H., Graham, S.C. and Deane, J.E. The lipid transfer protein Saposin B does not directly bind CD1d for lipid antigen loading. Wellcome Open Res. 2019, 4:117. (2019)
8. Graham, S.C., Nagar, B., Prive, G.G.and Deane, J.E. Molecular models should not be published without the corresponding atomic coordinates. Proc. Natl Acad. Sci. U.S.A. 116:11099-11100. (2019).
9. Hill, C.H., Cook, G.M., Spratley, S.J., Fawke, S. Graham, S.C. and Deane, J.E. The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure. Nat. Comms 9:151. (2018).
