Cell biology of neurodegeneration: function of a novel molecular chaperone network in protein trafficking

Project background

Molecular chaperones act in multiple cellular protein folding and remodelling processes to control diverse cellular functions. They are crucial in virtually all stages of the life of proteins from synthesis to degradation and are thus essential for maintaining protein homeostasis, with direct implications for human health and disease. This PhD project is focused on understanding the function of a novel molecular chaperone network that has the super molecular chaperone sacsin at its core. Sacsin is mutated in the rare neurological disorder Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay (ARSACS), with this project building on our recent work showing that when sacsin is absent microtubule-dependent trafficking of membrane proteins is disrupted (DOI: 10.1016/j.celrep.2022.111580).

What the studentship will encompass

The project will test the hypothesis that disrupted cell surface traffic and mislocalisation of specific proteins contributes to ARSACS molecular pathology, representing a potential target for therapeutic intervention. The specific objectives of the PhD project are to: 1) define the subset of proteins that require sacsin for normal localisation; 2) establish the mechanism by which sacsin modulates the transport of proteins; and 3) perform in silico drug repurposing analysis and test if identified compounds can rescue cell surface localisation of key neuronal proteins. To achieve these goals the student will utilise a portfolio of contemporary molecular cell biology skills ranging from genome editing to super-resolution confocal microscopy. They will also be trained in cutting-edge bioinformatic methods including for analysis of spatial transcriptomic data.

The project will be supervised by Prof. Paul Chapple and Dr. James Timmons. Prof. Chapple is a cell biologist whose research has concentrated on understanding the role of cellular stress and molecular chaperones in health and disease. This has included studies of multiple rare diseases and in particular neurodegenerative disorder, such as the ataxia ARSACS. Dr. Timmons is a bioinformatician with a strong interest in metabolic diseases and spatial transcriptomics.

The faculty of Medicine and Dentistry has state-of-the-art research laboratories and core facilities, including for cellular imaging and multi-omics, which will be utilised by the student. Moreover, Queen Mary University of London is one of the UK’s top research universities, with the vast majority (92%) of our research assessed as internationally excellent or world leading.

Requirements

Candidates are required to have a Bachelor’s degree (minimum 2:1) or Master’s degree in a relevant field, such as cell biology, molecular biology, neuroscience or genetics. Some knowledge of neurodegenerative disease will be beneficial, as would experience of bioinformatics data analysis.

How to apply

The deadline for applications is 16:00 (GMT) 2^nd December 2024. Interviews will be scheduled for the 2nd week of December 2024. To be considered for this PhD, please submit an application through our web portal: https://mysis.qmul.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RFQM-W6XF-01&code2=0016

For your application, please upload a CV (maximum 2 pages) and a Personal Statement (maximum 1 page) that should include: why you are interested in undertaking this project and what relevant existing skills, training, and knowledge you would bring to the project.

For informal inquiries please contact Prof. Paul Chapple (j.p.chapple@qmul.ac.uk).