University of Dundee

* SPRINT-MND/MS PhD Programme* Regulation and function of NEK1 kinase in Motor Neurone Disease

Mutations in the NEK1 kinase have recently been identified in patients with familial motor neurone disease (MND). NEK1 encodes a kinase of 1258 amino acids and previous studies have linked NEK1 activity to regulation of DNA repair pathways. How defects in DNA repair lead to MND is currently unknown. The project involves cutting-edge technologies carried out in a world-class institution to characterize the function of NEK1 in relevant neuronal systems. The project will also determine how mutations lead to MND, and analyse the impact of these mutations on cell responses to DNA damage. In particular biochemical and proteomic methodologies will be employed to discover key substrates of NEK1 whose phosphorylation by NEK1 is critical for motor neuron survival. The Rouse lab has an excellent track record in identifying new DNA repair proteins (SLX4, FAN1, MMS22, TONSL, for example), and in delineating the functions of these proteins from scratch. A major programme of on-going research is elucidating the role of novel kinases and phosphorylation events in DNA repair. The Muqit lab has a major interest in defining signal transduction pathways in neurodegenerative diseases most recently the role of the PINK1 kinase in Parkinson’s disease. On-going research combines state-of-the-art technologies in signal transduction with contemporary neuroscience methods including primary neuron culture systems and in vivo brain analysis.

References

Kenna KP, van Doormaal PTC, Dekker AM, Ticozzi N, Kenna BJ, Diekstra FP, van Rheenan W, van Eijk KR, Jones AR, Keagle P et al. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nature Genetics 2016; 48: 1037-42.

Lachaud C, Moreno A, Marchesi F, Toth R, Blow JJ, Rouse J. Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome stability. Science 2016; 351: 846-9.

Castor D, Nair N, Declais AC, Lachaud C, Toth R, Macartney TJ, Lilley DM, Arthur JS, Rouse J. Cooperative control of holliday junction resolution and DNA repair by the SLX1 and MUS81-EME1 nucleases. Mol Cell 2013; 52: 221-33.

Lai YC, Kondapalli C, Lehneck R. Procter JB, Dill BD, Woodroof HI, Gourlay R, Macartney TJ, Corti O, Corvol JC, Campbell DG, Itzen A, Trost M, Muqit MM. Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1. EMBO J 2015; 34: 28460-61.

Kazlauskaite A, Martinez-Torres RJ, Wilkie S, Kumar A, Peltier J, Gonzalez A, Johnson C, Zhang J, Hope AG, Peggie M, Trost M, van Aalten DM, Alessi DR, Prescott AR, Knebel A, Walden H, Muqit MM. Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation. EMBO Rep 2015: 16: 939-54. 

 

Prerequisites

Honours degree in Biochemistry, Molecular Biology or Neuroscience would be preferable.

Experience with biochemical techniques including tissue culture

Ability to work effectively in a team

Excellent communication skills and proficiency in English.

Please contact your intended supervisor to discuss the project and your suitability for it before submitting your application.

Application link:  http://www.edneurophd.ed.ac.uk/basic-neuroscience-genetics-neurones-and-networks/regulation-and-function-nek1-kinase-motor-neurone

The project is a part of SPRINT-MND/MS, a new Scotland-wide PhD scheme for research into motor neurone disease and multiple sclerosis. Projects, encompassing a wide range of topics including laboratory, clinical, and social sciences, are available at Aberdeen, Dundee, Edinburgh, Glasgow and St Andrews Universities. This exciting initiative provides a great opportunity for budding researchers in any field related to MND or MS to join Scotland’s network of world-leading scientists and health professionals. Find more information here: http://www.edneurophd.ed.ac.uk/sprint-mndms-phd-programme

Eligibility