MRes - Parkinson’s disease risk and lipid metabolism

Supervisors: Susanne Herbst and Dr Patrick Lewis

Department: Comparative Biomedical Sciences

Project Details

We are inviting applications for a research project studying the cell biology of Parkinson’s Disease (PD). Parkinson’s Disease is a neurodegenerative movement disorder that is characterised by the death of dopaminergic neurons in the brain. Defining the cellular pathways which lead to neuronal cell death is a central goal in PD research with the final aim of identifying druggable targets to treat the disease. Although the underlying cause of PD is unknown for most patients, genetic alterations that increase disease risk give insight into cellular disease mechanisms. One of the cellular pathways highlighted by genetic studies of PD is lysosomal lipid metabolism, sparked by the discovery that heterozygous mutations in beta-glucocerebrosidase (GBA) predispose to PD. GBA is a lysosomal enzyme which metabolises glucosylceramide into glucose and ceramide. PD-causing mutations decrease GBA enzymatic function, resulting in the lysosomal accumulation of GBA substrates. Notably, a number of other PD risk factors, such as LRRK2, also act at the lysosome and have been implicated in lipid metabolism. If the cellular mechanism by which GBA and LRRK2 cause lysosomal dysfunction overlap is unknown. This project aims to investigate the potential interplay between the PD risk factors GBA1 and LRRK2 at the level of lysosomal lipid metabolism.

Project aims:

  1. Investigate lipid droplet formation in GBA knock-out and LRRK2 knock-out cells
  2. Study if lysosomal lipid overload (as seen when GBA is not functioning) results in LRRK2 activation
  3. Investigate the interplay between GBA and LRRK2 function using chemical inhibitors

Core techniques: Cell culture, immunocytochemistry, confocal microscopy, SDS-PAGE and western blotting

References

  1. García-Sanz, Patricia, Lorena Orgaz, Guillermo Bueno-Gil, Isabel Espadas, Eva Rodríguez-Traver, Jaime Kulisevsky, Antonia Gutierrez, et al. 2017. “N370S-GBA1 Mutation Causes Lysosomal Cholesterol Accumulation in Parkinson’s Disease.” Movement Disorders: Official Journal of the Movement Disorder Society 32 (10): 1409–22.

  2. Schneider, Susanne A., Baccara Hizli, and Roy N. Alcalay. 2020. “Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism.” Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics 17 (4): 1378–92.

  3. Singh, Pawan Kishor, and Miratul M. K. Muqit. 2020. “Parkinson’s: A Disease of Aberrant Vesicle Trafficking.” Annual Review of Cell and Developmental Biology 36 (1): 100818–512.

Requirements

Essential

Desirable

  • Previous experience working with cultured cells or using molecular biology techniques.

This project will be full-time (12 months) commencing in October 2023. It will be based at RVC's Camden campus.

Funding

This project is partially funded: e.g. the lab will be covering the project costs, with the MRes student expected to meet the course fees and their living expenses.

You can find information on fees and funding online. A postgraduate master's loan may be available to help cover costs.

How to Apply

For more information on the application process and English Language requirements see How to Apply.

Deadline: 26th March 2023

We welcome informal enquiries - these should be directed to sherbst@rvc.ac.uk and plewis@rvc.ac.uk 

Interview date and location: TBC (May 2023)

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