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The biophysics of phase separation in motor neurone disease

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  • Full or part time
    Dr Rosie Staniforth
    Dr R Highley
    Dr A Parnell
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The majority of neurodegenerative conditions are characterised by pathological inclusions of aggregated protein and motor neurone disease (MND) is no exception. Two protein aggregates are pathognomonic of the disease: the best-studied protein that aggregates in MND is TDP43, but there exists a second, lesser understood intracellular inclusion referred to as the Bunina body, predominantly composed of the protease inhibitor cystatin C. The study of TDP43 has generated a vast literature pertaining to the pathogenesis of MND, yet it remains uncertain how these TDP43 aggregates are formed. Around 90% of TDP43 is found in the cell nucleus, shuttling between here and the cytoplasm, but in a subset of neurones in MND, it is cleaved, such that the C-terminal fragments lose the nuclear localisation signal and aggregate in the neuronal cytoplasm, depleting the cell of normal nuclear TDP43 (Neumann et al 2006, Science 314:130). Cystatin C is normally expressed to a high degree throughout the cytoplasm of motor neurones. However, when a Bunina body is formed, it appears that the cystatin C is sequestered into these inclusions, such that the level of cytoplasmic cystatin C is lower in residual neurones in MND than is seen in neurologically healthy controls (Fig. 1a). Scrutiny of raw expression data from residual motor neurones at post mortem suggests an increase in the number of mRNA transcripts for the CST3 gene which encodes cystatin C - a possible compensatory mechanism (Highley et al 2014, Neuropath. Appl. Neurobiol. 40, 670).

The aim of the project will be to characterise Bunina bodies from human tissue then reconstruct them in vitro and in cell lines using the recombinant proteins. The new model system will be used to interrogate the dynamics of liquid-liquid phase separation using state-of-the-art microscopy work in situ and specialist fractionation and structural biology techniques in vitro. A deeper understanding will allow selection of a targeted drug to inhibit assembly or promote a timely disassembly of the Bunina bodies in diseased motor neurones.

Funding Notes

RCUK equivalent home stipend rate per annum for 3.5 years
Home tuition fees for 3.5 years
£4,500 Research Training Support Grant
Funding will be awarded on a competitive basis to two of the following projects.
A first class or upper second class honours degree in a biological sciences subject or a related discipline, or a merit or distinction in a suitable MSc. Experience working in a research laboratory is desirable.

You should be applying to start your first year of study on a full-time or part-time PhD with the University in academic year 2020-21 (after 1 October 2020).

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