Developing an advanced microscopy platform to characterise neuronal internalisation and spreading of pathological protein aggregates

About the Project

PhD studentship in automated fluorescence microscopy to study intercellular aggregate spreading, Imperial College London

Applications are invited for a 4-year PhD studentship (funded at UK/home-fees level) in the Department of Brain Sciences at Imperial College London in the research group of Dr Yu Ye (www.ye-lab.co.uk).

Developing an advanced microscopy platform to characterise neuronal internalisation and spreading of pathological protein aggregates

The project is a multi-disciplinary PhD studentship based in Sir Michael Uren Hub at Imperial’s White City Campus.

The Department of Brain Sciences

The mission of the department is to develop and sustain a unique portfolio of translational research in neuroscience and mental health that is recognised internationally for scientific excellence, for leading innovation in patient care and for supporting the training of leaders for the next generation. Of relevance, The Department of Brain Sciences comprises the multidisciplinary UK Dementia Research Institute at Imperial and it hosts the Multiple Sclerosis and Parkinson's Tissue Bank, a national collection of central nervous system (CNS) tissue samples donated by individuals with multiple sclerosis (MS), Parkinson’s disease and related neuroinflammatory and neurodegenerative conditions.

The laboratory:

The research programme of Dr Yu Ye is focused on the interplay between protein homeostasis (proteostasis) and protein aggregation in model cellular systems. Using cutting-edge fluorescence imaging and analytical techniques, the lab seeks to uncover the molecular and cellular mechanisms of pathological aggregates. The laboratory has built two advanced microscope systems for live-cell and super-resolution imaging, and hosts a range of other bespoke equipment to support this project (http://www.ye-lab.co.uk/Equipments.html).

Background:

Aggregation of the protein alpha-synuclein (aS) is thought to cause Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and other disorders collectively known as alpha-synucleinopathies. Ours’ and others’ works have shown that aS aggregates from different alpha-synucleinopathies exhibit distinct toxicity and structure, potentially explaining pathological and phenotypic differences among these related diseases. However, resolving molecular differences at a statistically meaningful level would involve sampling a high number of cellular responses.

We propose to apply an advanced automated imaging approach to quantitatively study aggregate uptake and spreading between cells. Upon establishing an automated self-driving microscope routines for data acquisition, we will integrate this with our current analytical pipelines to quickly record and quantify the effect of aggregate spreading at a subcellular level. Using our recent published approach to perform super-resolution microscopy of aggregate features in live cells, we will examine how aggregates from PD dementia, non-demented PD and DLB induce different cellular responses in cell lines with knock-downs of specific PD-risk genes. Our overarching aim is to establish a detection system in live neurons that enables screening of candidate therapeutics that reduce pathological aggregate levels.

The project:

This PhD project is focused on establishing and applying advanced fluorescence imaging techniques to quantitatively study how pathological aggregates are internalised and spread between cells. To enable this, we have dedicated an advanced microscope fitted with a temperature and CO2-controlled chamber for prolonged multi-colour live cell imaging capable of running programs enabling long term imaging across multiple fields of view.

While a multi-disciplinary degree is not a requirement, the ideal PhD candidate will have a background in biophysics/bioengineering, neuroscience or biological chemistry with prior experience in image analysis/coding (e.g. Matlab, Python). The initial goal would be to test automated, event-driven data acquisition scripts to record high-quality datasets capturing the subcellular responses to different aggregate burdens. The candidate will then use these approaches to study how pathological aggregates from PD, PD dementia and DLB donors differ in their ability to be taken up by cells, and how efficiently they spread to other adjacent cells. Finally, the candidate will examine the knock-down effect on specific PD-risk genes on each of the aggregate types and examine therapeutic intervention potentials.

Studentship Details:

Students will be registered in the Department of Brain Sciences in the Faculty of Medicine.

The award is for 48 months (full time) and covers course fees at the Home rates (2025/26 fees £7,400 per annum) and a tax-free stipend starting at £22,780 per annum. Bench fees for this research (£10,000 per annum) is also covered. Non-UK/home-fee applicants, if successful, will be responsible for payment of fees at the overseas rate (currently £46,800.00 per annum). Funding for overseas fees is not provided.

Applicants must hold a First Class or an Upper Second Class degree (or equivalent overseas qualification) in a relevant STEM discipline, and Imperial would normally expect successful applicants to hold or achieve a Master's degree in a related field. Prior experience in neuroscience is not essential but experience with microscopy techniques, image analysis and programming would be preferred.

Applicants must also meet Imperial College’s English language requirements – further details can be found at https://www.imperial.ac.uk/study/pg/apply/requirements/english/.

Non-UK/home-fee applicants, if successful, will be responsible for payment of fees at the overseas rate (currently £46,800.00 per annum). Funding for overseas fees is not provided.

For informal enquiries please contact Dr Yu Ye (yu.ye1@imperial.ac.uk), attaching a copy of your CV. For application, please send a full CV, stating your nationality, and the full contact details of two academic referees.

The successful candidate is expected to write a detailed research plan ahead of start of PhD.

We regret that due to the large volume of applications received, we are only able to notify those shortlisted for interview. Applications will be considered throughout the year.