Studies of the dynamic structure, misfolding and inhibition of aggregation of the motor neurone disease associated protein, TDP-43

Project background

A 3-year Motor Neurone Disease Association (MNDA) funded PhD studentship is available to work with Dr Lisa Cabrita and Professor John Christodoulou in the Institute of Structural and Molecular Biology (ISMB), Department of Structural and Molecular Biology, University College London (UCL). Our Wellcome Trust-funded research programme is focused on understanding how proteins acquire their structure and avoid misfolding during synthesis, a process which occurs within all living systems. We apply a multi-disciplinary structural biology approach to our research by combining NMR spectroscopy, cryo electron microscopy and molecular dynamics simulations, together with biochemistry/biophysics approaches, to describe the structural and dynamical properties of the nascent polypeptide chain as it emerges from the ribosome.

An important consequence of proteins failing to adopt their biologically active structure, however, is that protein misfolding can occur, resulting in toxic cellular inclusions, which are implicated in many diseases. In motor neurone disease (MND) or amyotrophic lateral sclerosis (ALS), there is the progressive and premature loss of motor neurons within the central nervous system, which leads to muscle weakness, atrophy and ultimately fatal paralysis. The pathogenesis of MND/ALS is complex, however in ca. 90% of all cases, present within neurons are intracellular inclusions of aggregates of the protein, TDP-43. An understanding of the structure and dynamics of TDP-43 is an important step towards identifying disease mechanisms for potential therapeutic strategies.

Aim
This project aims to develop a detailed structural and dynamical understanding of the multi-domain protein, TDP-43, towards a high-resolution structural model of the protein in its biologically-active state and how it transitions towards toxic intracellular aggregates. The impact of known pathogenic mutations on the folding and stability of TDP-43 will also be investigated using both NMR spectroscopy and biophysics, and in which putative small molecule inhibitors of aggregation will also be explored. This structural biology project will use a wide range of experimental techniques, including molecular biology, protein expression/purification, NMR spectroscopy (in vitro and in-cell), biophysical strategies and molecular dynamics simulations.

Training and Support
The candidate will gain expertise in molecular biology, protein biochemistry, and biological NMR spectroscopy. The Christodoulou Laboratory is well equipped for all aspects of the research and is well supported by world-class facilities, and infrastructure available in the ISMB, including routine access to high field (700, 800, MHz) spectrometers. Regular access to 950 MHz spectrometers is also available from the nearby Francis Crick Institute. We also have strong collaborative links with the University of Florence (Prof Fabrizio Chiti), Birkbeck College (Prof Elena Orlova) and the University of Cambridge (Profs Michele Vendruscolo and Christopher Dobson).

Eligibility
This project will suit a highly motivated individual who has a strong desire to study protein folding, structure and misfolding. Applicants should have, or should expect to achieve, a first class or upper second-class degree in physical chemistry, biochemistry, or a related natural/biomedical science. Experience in NMR spectroscopy, molecular biology/recombinant protein production is also highly desirable. The proposed start date is 1 October 2016. Due to restrictions on funding, this MNDA-funded studentship is only open to UK/EU students.

Self-funded students: International or domestic self-funded PhD students with equivalent levels of qualifications are also welcome to apply for this project or related projects in the Christodoulou laboratory http://www.ucl.ac.uk/smb/christodoulou. Please note that both University and laboratory bench fees would also need to be self-funded. International students must have an excellent command of both written and spoken English. Applications can be made throughout the year.

To apply, please send your CV and a research statement to Prof Christodoulou by 31st August 2016. For further information about the project, please contact Professor John Christodoulou ([Email Address Removed]) or Dr. Lisa Cabrita ([Email Address Removed]).