Neurodegeneration is a feature of many debilitating, incurable diseases with underlying defects in RNA metabolism (e.g. spinal muscular atrophy, ALS), but the link between RNA biology and neuronal death is poorly understood.
A key player in eukaryotic RNA biology and gene expression is the RNA exosome, a ubiquitously expressed, multi-subunit ribonuclease complex that participates in maturation and/or quality control of almost every RNA molecule in all cell types. Importantly, an intact exosome is also critical for the assembly of the ribosome, the essential RNA-protein machinery that makes all cellular proteins. Defects in ribosome production cause stabilisation of the tumour suppressor p53, leading to cell cycle arrest and apoptosis.
Highly tissue-specific childhood-onset neurodegenerative diseases such as spinal muscular atrophy, pontocerebellar hypoplasia and cerebellar atrophy can be caused by mutations in genes encoding core subunits of the RNA exosome (EXOSC2, EXOSC3, EXOSC8 and EXOSC9). For some of these diseases, the human phenotype was recapitulated in zebrafish models, which revealed cerebellar atrophy due to apoptosis of neuronal cells. RNA sequencing of reprogrammed patient neuronal progenitor cells (NPCs) further detected significant changes in genes involved in neuronal development or degeneration.
Importantly, children with these rare genetic disorders often fail to obtain a correct diagnosis due to nonspecific neurological symptoms, delaying appropriate treatment. In this PhD project, the student will therefore employ a combination of cell biology, biochemistry and molecular biology techniques to characterise the effects of disease-linked mutations in EXOSC2, EXOSC3, EXOSC8 and EXOSC9 on RNA exosome levels, stability and its interaction with various RNA substrates. Using stably transfected human cell lines (expressing RNAi-resistant or CRISPR-generated mutant forms of the individual exosome subunits) and the established NPC and zebrafish disease models, the student will further asses how these exosome mutations affect ribosome production, p53-dependent signalling pathways and survival of neurons and other cells. Chemicals known to increase ribosomal production (e.g. mTOR-activators) may overcome the predicted defects due to the mutated exosome subunit. The student will therefore also determine whether use of these and other drugs could be a valid therapeutic approach.
Understanding how distinct patient-derived mutations in the ubiquitously expressed, multi-subunit RNA exosome cause tissue-specific neurodegenerative diseases will enable future development of specialised, information-led therapeutic approaches.
This PhD project with the main base at Newcastle University and an external project at the University of Cambridge will provide training in a wide range of techniques. The successful PhD candidate will also benefit from the PhD development programme at the Newcastle University Graduate School, which offers a variety of core and transferable skills courses and a flourishing postgraduate culture. Career progression will be monitored yearly by an academic progression panel and a designated PhD mentor. The student will also be able to present their data at both national and international meetings.
For further information see these websites: https://www.ncl.ac.uk/camb https://www.ncl.ac.uk/camb/staff/profile/claudiaschneider.html#background https://www-neurosciences.medschl.cam.ac.uk/horvathlab
Informal enquiries may be made to [email protected]
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
Schneider, C. and Tollervey, D. (2013) Threading the barrel of the RNA exosome. Trends in biochemical sciences, 38, 485-493.
Pelava, A., Schneider, C. and Watkins, N.J. (2016) The importance of ribosome production, and the 5S RNP-MDM2 pathway, in health and disease. Biochemical Society transactions, 44, 1086-1090.
Müller, J.S., Giunta, M. and Horvath, R. (2015) Exosomal Protein Deficiencies: How Abnormal RNA Metabolism Results in Childhood-Onset Neurological Diseases. J Neuromuscul Dis, 2, S31-S37.