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

Department of Brain Sciences at Imperial

PhD studentship in advanced fluorescence microscopy to study Parkinson’s disease and dementia with Lewy bodies, Imperial College London

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

The project is 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 techniques, the lab seeks to uncover the molecular and cellular mechanisms of degradation of pathological aggregates, and how malfunction of the ubiquitin-proteasome system may contribute to neurodegenerative disorders. 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), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB) and other disorders collectively known as alpha-synucleinopathies. Such protein aggregates are thought to harm cellular systems by, e.g. penetrating cell and organelle membranes, induce oxidative and mitochondrial stress, and spreading to adjacent cells. 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 alpha-synucleinopathies. However, resolving differences in aggregate features at a statistically meaningful level would involve sampling a high number of cellular responses.

We propose to apply an advanced imaging approach to quantitatively study aggregate uptake and spreading between iPSC-differentiated neurons, linking the propagating ability of disease-specific aggregates to their distinct molecular features. We will then use this live-neuron aggregate imaging system to examine the effect on aggregate level and trafficking by knock-down of specific PD-risk genes. A recent study demonstrated GPNMB to promote interaction, uptake and pathology of aS aggregates. Using our recent published approach to perform super-resolution microscopy of aggregate features in live cells, we will examine how aggregates from PD, PDD, and DLB differ at the molecular level in their response to risk-gene inactivation. 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 iPSC-neurons and other cell types. To enable this, we have dedicated an advanced microscope fitted with a temperature and CO₂-controlled chamber for prolonged multi-colour live cell imaging. The ideal PhD candidate will have a background in biophysics/bioengineering or biological chemistry with prior experience in image analysis/coding (e.g. Matlab, Python). First validating the microscope and establishing quantitative analysis approaches, the candidate will use these approaches to study how pathological aggregates from PD, PDD, and DLB donors differ in their ability to be taken up by neurons, how they may differ in escaping degradation and how efficiently they spread to other adjacent cells. Using siRNA and antisense oligonucleotides, the candidate will finally 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.

Ideal start date for the studentship is the 1st of October, 2024. Position will be open until filled.

The award is for 48 months (full time) and covers course fees at the Home/EU rates (2024/25 fees £7,280 per annum) and a tax-free stipend starting at £21,000 per annum. Bench fees for this research (£10,000 per annum) is also covered.

Applicants must hold (or obtain by October 2024) 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.

Non-EU applicants, if successful, will be responsible for payment of fees at the overseas rate (currently £ 45,850.00 per annum). Funding for overseas fees is not provided.

For informal enquiries please contact Dr Yu Ye ([email protected]). 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.