EMC-2024-3_McGurk: Elucidating how the poly(ADP-ribose) polymerases control the progression of motor neuron disease.


   Centre for Clinical Brain Sciences

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Dr L McGurk, Dr Greg Findlay  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

THIS PROJECT WILL BE BASED AT THE UNIVERSITY OF DUNDEE

This project is on offer as part of the studentship scheme of the Euan MacDonald Centre for Motor Neuron Disease Research. The Euan MacDonald Centre is a multi-disciplinary network of MND researchers across Scotland. A choice of six projects is on offer now for a start date in Autumn 2024, at the University of Edinburgh, St Andrews or Dundee. For more information see www.euanmacdonaldcentre.org/phd-scheme. Euan MacDonald Centre students join our network of >200 MND researchers across Scotland and will have the opportunity to meet people living with MND, participate in academic and public engagement events led by the Centre. To view all the projects offered under this scheme please search for reference numbers EMC-2024-1 to EMC-2024-6.

We aim to develop therapeutic strategies for amyotrophic lateral sclerosis (ALS) by elucidating how the RNA-binding protein TDP-43, which is central to ALS, causes disease. In 90% of individuals diagnosed with ALS, TDP-43 is mislocalised to the cytoplasm where it forms phosphorylated and insoluble aggregates composed of full-length protein and cleavage products. This causes both gain-of-function and loss-of-function effects including a loss of TDP-43-controlled RNA splicing and neurological decline. We aim to understand how TDP-43 builds up in the cytoplasm as this may lead to therapies that preventing or reversing TDP-43 mislocalisation to the cytoplasm and mitigate disease symptoms. We discovered that genetic and pharmacological inhibition of an enzyme called Tankyrase, ameliorates TDP-43 toxicity in rat primary neurons and in neurons of Drosophila melanogaster (Drosophila). Tankyrase is a cytoplasmic enzyme that links poly(ADP-ribose) on to target proteins, canonically the poly(ADP-ribose) targets the protein for ubiquitination and proteasomal degradation. By contrast, our work indicates that Tankyrase binds to TDP-43 and rather than being degraded TDP-43 is stabilised. A tantalising hypothesis is that Tankyrase binds to TDP-43 and because TDP-43 is stabilised it abnormally builds up into the aggregates that are observed in disease. Importantly Tankyrase also forms aggregates in spinal cord motor neurons. We now aim to define how Tankyrase activity is involved in ALS. In this project the student will define how key point mutations in Tankyrase control TDP-43 aggregation and motor neuron survival in Drosophila and in iPSC-derived neurons. Understanding how Tankyrase controls motor neuron death in ALS will be the foundation for future research into novel therapeutic strategies.

Suitable first degree subjects: molecular biology, neuroscience, biochemistry. Essential and/or desirable skills and experience: Western blotting, immunoprecipitation, protein purification, cell culture. 

Biological Sciences (4) Medicine (26)

Funding Notes

The studentship comprises 42 months (3.5 years) stipend payments at the standard UKRI rate, tuition fees and an allowance of £10K per year for three years for consumables and travel. The studentship is open to applicants worldwide. Students will register for the most appropriate degree programme at the University where the project is being offered. It is the applicants’ responsibility to ensure they meet the eligibility requirements for postgraduate study at their chosen University, in terms of academic achievements and English language proficiency.

References

1. Francois-Moutal, L., Scott, D.D., Ambrose, A.J., Zerio, C.J., Rodriguez-Sanchez, M., Dissanayake, K., May, D.G., Carlson, J.M., Barbieri, E., Moutal, A., et al. (2022). Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology. Scientific reports 12, 8140. 10.1038/s41598-022-12191-8.
2. McGurk, L., Rifai, O.M., and Bonini, N.M. (2020). TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2. J Cell Sci 133. 10.1242/jcs.245811.
3. McGurk, L., Gomes, E., Guo, L., Shorter, J., and Bonini, N. (2018). Poly(ADP-ribose) engages the TDP-43 nuclear-localization sequence to regulate granulo-filamentous aggregation. Biochemistry 57, 6923-6926 10.1021/acs.biochem.8b00910.
4. McGurk, L., Rifai, O.M., and Bonini, N.M. (2019). Poly(ADP-Ribosylation) in Age-Related Neurological Disease. Trends Genet 35, 601-613. 10.1016/j.tig.2019.05.004.
5. McGurk, L., Gomes, E., Guo, L., Mojsilovic-Petrovic, J., Tran, V., Kalb, R.G., Shorter, J., and Bonini, N.M. (2018). Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization. Molecular cell 71, 703-717 e709. 10.1016/j.molcel.2018.07.002.

How good is research at University of Edinburgh in Psychology, Psychiatry and Neuroscience?


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

Click here to see the results for all UK universities

Where will I study?

Search Suggestions
Search suggestions

Based on your current searches we recommend the following search filters.