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Dimerization and RNA-binding dynamics of TDP-43 during stress responses in neurons

  • Full or part time
  • Application Deadline
    Monday, January 07, 2019
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

RNA-binding proteins (RBPs) are known to play an important role in
neurons, where they are involved heavily in maintaining normal cell
function. Mis-behavior of those proteins can be caused by cellular stress
or dysregulation of protein homeostasis, which leads to protein
aggregation with consequent damage to neurons. One such RBP is
TDP-43, which has a high propensity to form aggregates. These
aggregates are observed in neurons of ageing and neurodegenerative
conditions. Under basal conditions, TDP-43 shuttles between nucleus
and cytoplasm transporting its targeted RNA molecules to neuronal
extensions for further processing. When the cells are stressed, TDP-43
brings target RNAs into an organelle called a stress granule where they
are protected from degradation during stress. Stress granules are
dynamic structures that are quickly dissembled when the stress is
resolved. This mechanism ensures a rapid recovery of protein production
for neurons recovering from stress. Several studies have indicated that
interaction with RNA has an impact on the clustering properties of
TDP-43. However, the nature of the TDP-43 cluster and the mechanism
involved in clustering remain largely unclear.
This project will address the following key questions:
• What mechanisms are involved in the basal activity of TDP-43?
• What are the molecular and cellular processes that contribute to
TDP-43 aggregation?
• How do different functional domains of TDP-43 contribute to the
stress response and recovery period?
The student will use wide range of biochemical and biophysical analyses
to characterize TDP-43 solubility, self-association and structural changes
under different conditions. These will be complemented with cell culturebased
studies where the dynamics of TDP-43 protein movement will be
monitored using live-cell imaging. The student will also use primary
neurons and in vivo models to validate the findings.

Funding Notes

This is a 4 year fully-funded studentship part of the BBSRC White Rose Doctoral Training Partnership in Mechanistic Biology. The studentship covers: (i) a tax-free stipend at the standard Research Council rate (around £15,000 per year), (ii) tuition fees at UK/EU rate, (iii) research consumables and training necessary for the project.

Entry requirements: At least an upper second class honours degree, or equivalent in any biological, chemical, and/or physical science. Students with mathematical backgrounds who are interested in using their skills in addressing biological questions are also welcome to apply.

References

Eligibility: The studentships are available to UK and EU students who meet the UK residency requirements. Students from EU countries who do not meet the residency requirements may still be eligible for a fees-only award. Further information about eligibility for Research Council UK funding

Shortlisting: Applicants will be notified if they have been selected for interview in the week commencing on Monday 28 January 2019.

Interviews: Shortlisted applicants will be invited for an interview to take place in the Department of Biology at the University of York on Wednesday 6 and Thursday 7 February 2019. As part of the interview process candidates will be asked to give a 5 minute presentation on a research project carried out by them.

How good is research at University of York in Biological Sciences?

FTE Category A staff submitted: 44.37

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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