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.

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