Molecular mechanisms of genetic and infectious disease
Pathogenesis of rare inherited lipid disorders
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.
Host-pathogen interactions during Shigella infection
Diseases caused by bacteria, viruses and other parasites are major causes of death, disability, and social and economic disruption for millions of people. Our ability to effectively treat infectious diseases is being progressively depleted due to increasing resistance of microbes to antimicrobial drugs. A top priority today is the development of new low-cost drugs that can replace those that are becoming ineffective. An essential part of developing new therapeutics is a clear molecular understanding of how pathogens evade our immune defences and hijack our cellular components.
Our research focuses on the bacterial pathogen Shigella flexneri. This pathogen invades cells of our digestive tract and hijacks components of the actin polymerization pathway in order to aid its movement within our cells and allowing it to spread directly from cell to cell. In this way Shigella can limit its detection by our immune system. As an extra defence S. flexneri produces proteins that specifically disarm the intracellular immune response to pathogens. We study the structure, interactions and regulation of Shigella virulence proteins and the host proteins they target.
The Deane lab is currently hiring postdoctoral researchers.
Spratley, S.J., Hill, C.H., Viuff, A.H., Edgar, J.R., Skjødt, K. and Deane JE. Molecular mechanisms of disease pathogenesis differ in Krabbe disease variants. Traffic (in the press) (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).