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TDP-43 The Key protein for finding a cure for Motor Neurone Disease


Institute of Integrative Biology

About the Project

Motor neurone disease is a progressive, fatal neurological disorder with no known cure. It is characterised by selective loss of motor neurons in the spinal cord and cortex. Over 90% of MND (ALS) cases, both sporadic and familial, feature TDP-43-positive inclusions in the cytoplasm of affected neurons. Most MND patients die within 3-10 years due to respiratory failure. Understanding the molecular mechanism of MND and finding a therapeutic solution to remedy the disease-causing properties is our goal.

TAR DNA binding protein-43 (TDP-43), has multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. Its ability to bind UG-rich RNA is very important for normal localisation of TDP-43 in the nucleoplasm. Cytoplasmic mis-localisation and elevated half-life are characteristics of mutant TDP-43. ALS-associated TDP-43 mutations in the central nucleic acid binding RRM domains lead to increased thermal stability and elevated half-life in a TDP-43 disease cell model. Full length TDP-43 has been purified at Liverpool recently enabling SAXS measurements that hold promise for structure determination of full-length TDP-43. This is a major breakthrough in understanding the molecular mechanism of MND and finding a therapeutic solution to remedy the disease-causing properties of this critical protein.

The student will build on this success in a multidisciplinary programme using molecular biology, protein chemistry, bioinformatics, protein crystallography and Small angle X-ray scattering. Required ’wet-lab’ facilities for the project (e.g. cloning, expression and purification of proteins) are available at our institution. Additionally, UoL has a combined SAXS/MX facility on a super bright in-house X-ray generator FR-E+ and a crystallization robot.

Candidates must have, or expect to gain, a first or strong upper second class degree (or equivalent) in a relevant discipline.

Applications will be reviewed until a suitable candidate is appointed.

Funding Notes

The project is open to both UK and International students with their own funding/scholarship. Potential applicants are encouraged to contact the Principal Supervisor directly to discuss their application and the project.

Assistance will be given to those who are applying to international funding schemes.

The successful applicant will be expected to provide the funding for tuition fees and living expenses as well as research costs of £3000 per year.

Details of costs can be found on the University website: View Website

References

Disease causing mutants of TDP-43 nucleic acid binding domains are resistant to aggregation and have increased stability and half-life Austin, J.A. et al., (2014) PNAS, doi: 10.1073/pnas.1317317111.

Abnormal TDP‐43 function impairs activity‐dependent BDNF secretion, synaptic plasticity, and cognitive behavior through altered Sortilin splicing (2019) Jason Y Tann, Lik‐Wei Wong, Sreedharan Sajikumar, Carlos F Ibáñez EMBO J. 38(5): e100989.

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