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Janet Deane

The role of aberrant lipid processing in neurodegenerative disease

Elucidating how cellular membranes are maintained through lipid recycling in the lysosome, and how disruptions to this can cause severe neurodegenerative diseases.

Lipids are crucial molecules for fundamental cellular processes including cell division, autophagy and immunity. A specific subset of lipids, known as glycosphingolipids, are degraded in the lysosome and the products of this degradation play critical roles in the regulation of apoptosis and expression of genes important for healthy aging. Defects in the processing of sphingolipids are responsible for a range of diseases including neurodegeneration, metabolic diseases and cancers. The most acute of these is a family of diseases known as sphingolipidoses, several of which are severe, early-onset neurodegenerative diseases.

Our research focuses on a rare autosomal recessive disorder, Krabbe disease, which primarily affects infant children. It is caused by deficiencies in the enzyme galactocerebrosidase (GALC), which is produced in the ER-Golgi complex and then traffics to the lysosome where it is essential for lipid recycling. Defects in GALC lead to the accumulation of cytotoxic metabolites that elicit complex, and still only partially understood, cellular events that result in apoptosis of myelin-forming cells and progressive demyelination.

We use a range of techniques to better understand sphingolipid processing defects that cause Krabbe disease. Our recent structures of GALC provide new insight into the catalytic mechanism of GALC and the molecular role of pathogenic mutations. We have also developed a range of cell-based assays to analyse the molecular mechanisms underlying the pathogenesis of a series of disease-causing mutations in GALC including misfolding, altered post-translational modification and catalytic defects.

            Deane 2016 a

 

 

 

Deane lab

The Deane lab is currently hiring postdoctoral researchers.

Key papers:

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).

Hermann C, van Hateren A, Trautwein N, Neerincx A, Duriez PJ, Stevanovic S, Trowsdale J, Deane JE, Elliott E & Boyle LH. TAPBPR alters MHC class I peptide presentation by functioning as a peptide exchange catalyst. eLife 10.7554/eLife.09617 (2015).

Hill, C.H., Viuff, A.H., Spratley, S.J., Salamone, S., Christensen, S.H., Read, R.J., Moriarty, N.W., Jensen, H.H. and Deane, J.E. Azasugar Inhibitors as Pharmacological Chaperones for Krabbe Disease. Chemical Science 6, 3075-3086, DOI: 10.1039/C5SC00754B (2015).

Hill, C.H., Graham, S.C., Read, R.J. and Deane, J.E. Structural snapshots illustrate the catalytic cycle of β-galactocerebrosidase, the defective enzyme in Krabbe disease. Proc. Natl Acad. Sci. USA. 110, 20479–20484 (2013).

 

Dr Janet Deane

Royal Society University Research Fellow

Department of Pathology

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

Sam Spratley · Rui Mauricio

Funding

The Royal Society

Wellcome Trust

Medical Research Council