The Glycosphingolipid Code: How do altered protein-lipid interactions drive neurodegenerative disease?

Summary

Rare, early-onset neurodegenerative diseases can provide vital new insights into complex, late-onset diseases such as Alzheimer's and Parkinsons diseases. There is substantial evidence linking mutations associated with a family of rare diseases, called sphingolipidoses, to the development of Parkinsons disease. Sphingolipidoses are caused by defective processing of a special class of lipids known as sphingolipids.

These diseases cause catastrophic changes in cell function leading to rapid neurodegeneration and death. Sphingolipids play critical roles in membrane protein function, cell signalling and cell adhesion. Despite the established link between defects in sphingolipid metabolism and severe neurodegeneration, the mechanisms underlying this process remain poorly understood.

Project aims

This PhD project focusses on defining the molecular mechanisms linking sphingolipid-protein interactions to neurodegeneration.

Our lab uses multidisciplinary approaches to tackle these questions including developing CRISPR-based models of human disease, monitoring cellular changes via proteomic and lipidomic analysis, measuring protein-protein and protein-lipid interactions and determining high-resolution 3D structures. 

This PhD project aims to address two key questions in the field of protein-lipid interactions: 

• Why do we have such a broad range of different sphingolipids?
• Do the different lipids have specific roles in altering membrane protein function?

We have substantial published and unpublished data identifying which proteins bind to different sphingolipids. We now want to characterise these interactions functionally and structurally. We will use biochemical and structural approaches including liposome-pulldowns, X-ray crystallography and molecular dynamics simulations to define these interactions.

We will then exploit the insights gained from these structures and the expertise in the lab in cell-based models of diseases to understand how these interactions drive disease phenotypes.

Contact details

Professor Janet Deane - jed55@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD