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Elucidation of structure-function relationship of individual disease relevant protein aggregates in motor neuron disease using single molecule and super resolution imaging

  • Full or part time
  • Application Deadline
    Wednesday, January 29, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Aggregation and deposition of specific protein(s) are common hallmark of several neurodegenerative disorders including motor neuron disease (MND). Aggregation of proteins such as FUS, TDP-43, C9orf72, SOD1 are closely linked with MND initiation and progression. However, it is not known which isoforms of these aggregated species spread through the brain by infecting and destroying nerve cells in their path, causing the patient’s symptoms to get progressively worse. It is therefore essential to establish which type of aggregates are actually present in human and what their structure is and how they contribute in disease progression.

These protein aggregates present in human are highly heterogeneous and present in very low concentrations, preventing examination by conventional bulk approaches. Moreover, the metastable nature and high heterogeneity of protein aggregates in the actual disease presents a significant challenge for high resolution characterisation. Therefore, to understand the role of these protein aggregates during disease initiation and progression, we will use a combination of patient derived cellular models and ultra-sensitive imaging techniques to study individual protein aggregates involved in MND. 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 single molecule and super resolution imaging-based methodologies, we will identify and quantify the concentration of disease relevant endogenous aggregates, and investigates their size, structures and compositions formed at different stages of disease. We will determine if there is any post-translational modification and mutation in these proteins playing a larger role in disease progression. Subsequently we will map the structure-toxicity relationship by measuring toxicity in combination with their morphology (Nature Comm 2019, 10, 1541). We have developed a method to image single protein aggregates with 20-30 nanometre resolution (Acta Neuro Comm 2019, 7, 1-13). By refining and expanding previously developed imaging based biophysical assay, we will determine the nature of individual protein aggregates form in disease relevant models and compare with protein aggregates forms cellular models derived from healthy individuals and determine the role of different species in disease progression. Finally, we will develop a platform to measure the efficacy of potential disease modifying drugs by measuring their ability to reduce protein aggregate induced toxicity.

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:
These studentships will be 42 months in duration, and include home fee and stipend at UKRI rate.

Eligibility:
Candidates must have a first or upper second class honors degree or significant research experience. Experience with single molecule microscopy or neuornal cell culture would be highly advantageous, but not essential.

Enquiries:
Interested candidates should in the first instance contact Dr Suman De ()

PLEASE NOTE: This project is also open to other schemes within the University of Sheffield, which are currently being advertised.


References

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.

Deadline for applications is 5pm on Wednesday 29th January 2020. Late applications will not be accepted. Interviews are scheduled to be held on Tuesday 25th February 2020.

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