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Cambridge Institute for Medical Research

 

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, The Royal Society

Research Group Members: Iain Hay, Shannon McKie, Holly Monkhouse, Alex Nicholson, Emily Smith 


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

Key publications: 

 

Viuff AH, Salamone S, McLoughlin J, Deane JE & Jensen HH. The bicyclic form of galacto-noeurostegine is a potent inhibitor of β-galactocerebrosidase. ACS Med. Chem. Lett. 12: 56-59 (2021)

Hay IM, Fearnley GW, Rios P, Köhn M, Sharpe HJ & Deane JE. The receptor PTPRU is a redox sensitive pseudophosphatase. Nat. Comms 11:3219 (2020)

Shamin M, Benedyk TH, Graham SC & Deane JE. The lipid transfer protein Saposin B does not directly bind CD1d for lipid antigen loading. Wellcome Open Res. 2019, 4:117 (2019)

Hill CH, Cook GM, Spratley SJ, Fawke S, Graham SC & Deane JE. The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure. Nat. Commun. 9:151 (2018)

Spratley SJ & Deane JE. New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones. J Neurosci. Res. 94:1203-19 (2016)

Spratley SJ, Hill CH, Viuff AH, Edgar JR, Skjødt K & Deane JE. Molecular mechanisms of disease pathogenesis differ in Krabbe disease variants. Traffic 17, 908-922 (2016)

Hill CH, Viuff AH, Spratley SJ, Salamone S, Christensen SH, Read RJ, Moriarty NW, Jensen HH & Deane JE. Azasugar Inhibitors as Pharmacological Chaperones for Krabbe Disease. Chem. Sci. 6, 3075-3086, DOI: 10.1039/C5SC00754B (2015)

Hill CH, Graham SC, Read RJ & Deane JE. Structural snapshots illustrate the catalytic cycle of β-galactocerebrosidase, the defective enzyme in Krabbe disease. Proc. Natl Acad. Sci. USA. 110, 20479–20484 (2013)

Wellcome Trust Senior Research Fellow

Contact Details

jed55@cam.ac.uk
01223 762815
Takes PhD students
Available for consultancy