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Janet Deane

The role of sphingolipids in health and disease

The cell surface is decorated with proteins and lipids that mediate cell-cell contacts and trigger signalling pathways. An important class of lipids enriched at the plasma membrane are glycosphingolipids (GSLs), which play critical roles in membrane structure, host–pathogen interactions, cell–cell recognition and modulation of membrane protein function. Imbalances in 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. I seek to define the molecular mechanisms by which altered GSL metabolism perturbs cellular functions causing disease.

Fig1_GALC_overview

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 (Hill, et al. Nat. Commun. 2018). 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.

Fig2_CD1

The role of sphingolipids in host-pathogen pathways

Several pathogens rely on host sphingolipids to promote their virulence. For example, pathogens bind ceramide-rich membrane domains and surface-exposed GSLs during cell invasion, and they manipulate host sphingolipid pathways to promote their intracellular growth. Bacterial hijacking of host pathways has been a long-term interest in the lab and recently we have expanded this work, via a collaborative project, looking at viral hijacking of sphingolipid pathways.

Deane lab

Key papers:


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)

Mauricio RP, Jeffries CM, Svergun DI, Deane JE. The Shigella Virulence Factor IcsA Relieves N-WASP Autoinhibition by Displacing the Verprolin Homology/Cofilin/Acidic (VCA) Domain. J. Biol. Chem. 292:134-145 (2017)

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)

 

Janet Deane 

Dr Janet Deane

Royal Society University Research Fellow

Department of Clinical Neuroscience

e-mail: jed55@cam.ac.uk

01223 762 815

Plain English

Our cells can be thought of like a house: there are different rooms for different purposes. In the cell, these ‘rooms’ are known as organelles and the ‘walls’ are made of lipids. But cells are self-repairing and can synthesize, breakdown and recycle their own lipids. When lipid recycling becomes defective it results in severe human diseases, often due to rapid and fatal neurodegeneration. Our lab uses a range of techniques to probe how lipids are recycled in the cell and what happens when this recycling breaks down.

 

Group members

 Maria Shamin

Funding

The Royal Society

Wellcome Trust

Medical Research Council