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Studying protein aggregation in patient derived cellular models of Amyotrophic lateral sclerosis (ALS)


Project Description

Aggregation and deposition of specific protein(s) are common hallmark of several neurodegenerative disorders including ALS. Aggregation of several proteins such as FUS, TDP-43, C9orf72, SOD1 are closely linked with ALS initiation and progression. However, it is not known which isoforms of these aggregated species spread through the human brain by infecting and destroying neuronal cells in their path, causing the patient’s symptoms to get progressively worse. These protein isoforms are highly heterogeneous and present in very low concentrations, preventing examination by bulk approaches.
To understand the role of these proteins during disease initiation and progression, we will use a combination of patient derived cellular models and sensitive imaging techniques to study individual protein aggregates involved in ALS. Modelling of these disease in reprogrammed cellular systems has the potential to inform our understanding of the more complex form of the disease, while allowing for reductionist approaches toward elucidating complex biological interactions between disease pathways. Using state-of-the-art methodologies, (Nature Comm 2019, 10, 1541, Brain Communication 2020, Acta Neuro Comm 2019, 7, 1) we will identify and quantify the concentration of disease relevant endogenous aggregates, and determine their size, structures and compositions formed at different stages of disease and determine how structure f individual species control its function. We will also determine the nature of aggregates which present in human and compare with protein aggregates forms cellular models derived and determine the role of different species in disease progression.
The research involves cutting edge microscopy techniques through cross-disciplinary collaborations between the research groups of Suman De and Laura Ferraiuolo. At the end of this PhD project the student will have obtained practical skills of cell culture, super resolution and single molecule microscopy, data analysis as well as analytical, interpersonal and project management skills.

Funding Notes

Funding:
Fully funded project. RCUK equivalent home stipend rate.

Entry Requirements:
Candidates must have a first or upper second class honors degree or significant research experience. This studentship is only for UK/EU student.

References

Enquiries:
Interested candidates should in the first instance contact Dr Suman De ([email protected])

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Neuroscience' as the department.

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