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SOD1 The Key protein for finding a cure for familial Motor Neurone Disease

  • Full or part time

    Prof S Hasnain
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

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. Around 10% of the ALS cases are familial with ~20% of them arising from mutations in the sod1 gene, with most severe and common mutation being A4V. 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.

Cu/Zn binding superoxide dismutase is a homo-dimeric protein with an intra-subunit disulphide bond. This protein is responsible for converting harmful free superoxide radicals to hydrogen peroxide and oxygen in the body. Extensive structural studies have established that disease-causing mutations in SOD1 reduce the ability of protein to fold, bind metal cofactors and form the disulphide bond. As a result, mutant SOD1 is prone to misfolding and aggregation. Global efforts to correct this ‘gain-of-function’ have led to identification of a variety of ‘ligand-binding pockets’ that are suitable for drug development. Ebselen, an organoselenium compound with strong antioxidant activity, has been shown to rescue SOD1 from aggregation, especially in the A4V mutant. This discovery is the starting point for guiding discovery of the next generation of compounds aimed at stabilizing SOD1 mutants.

The student will build on this success in a multidisciplinary programme using molecular biology, protein chemistry, protein crystallography and human cell line assays. 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.

A tuition fee bursary may be available for well qualified and motivated applicants with First class degree.

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

References

The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation Capper, M. J., (2018), NATURE COMMUNICATIONS, 9; doi:10.1038/s41467-018-04114-x.

Ligand binding and aggregation of pathogenic SOD1. Wright G.S. et al., (2013) Nature Communications 4, 1758 [DOI: 10.1038/ncomms2750].

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