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MRC DiMeN Doctoral Training Partnership: Towards specialised treatments for childhood-onset neurological diseases caused by abnormal RNA metabolism


MRC DiMeN Doctoral Training Partnership

Newcastle United Kingdom Biochemistry Cancer Biology Cell Biology Developmental Biology Genetics Molecular Biology Neurology Neuroscience Structural Biology

About the Project

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, together with co-factors, 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, EXOSC5, 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 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, EXOSC5, EXOSC8 and EXOSC9 on RNA exosome levels, stability and its interaction with various RNA substrates and co-factors. 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 national and international meetings.

Click here for further information:

https://www.ncl.ac.uk/medical-sciences/research/institutes/biosciences

https://www.ncl.ac.uk/medical-sciences/people/profile/claudiaschneider

@CBCC_NCL, @CSchneiderNCL

https://www-neurosciences.medschl.cam.ac.uk/horvathlab @HorvathLab

http://genome.sheffield.ac.uk/people/dr-emma-thomson @ThomsonRNALab

Funding Notes

Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. 

Informal enquiries may be made to .


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

Müller, J. S., Burns, D. T., Griffin, H., Wells, G. R., Zendah, R. A., Munro, B., Schneider, C., & Horvath, R. (2020). RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels. Life science alliance, 3(8), e202000678. https://doi.org/10.26508/lsa.202000678
Pelava, A., Schneider, C., & Watkins, N. J. (2016). The importance of ribosome production, and the 5S RNP-MDM2 pathway, in health and disease. Biochemical Society transactions, 44(4), 1086–1090. https://doi.org/10.1042/BST20160106
Müller, J. S., Giunta, M., & Horvath, R. (2015). Exosomal Protein Deficiencies: How Abnormal RNA Metabolism Results in Childhood-Onset Neurological Diseases. Journal of neuromuscular diseases, 2(Suppl 2), S31–S37. https://doi.org/10.3233/JND-150086

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