Post-transcriptional gene regulation relies on the fine control of messenger RNA (mRNA) metabolism. The physical organisation and control of this process is not fully understood, resulting in many unanswered questions about the fundamental process of gene regulation in mammalian cells. We have identified novel mobile, lipid-based vesicles with probable functions in mRNA metabolism. Further analysis of the vesicles’ structure and function will add to the understanding of the cellular organization of RNA metabolism.
The control of RNA processing and transport is vital for the correct functioning of mammalian cells. Furthermore, it is increasingly apparent that defects in the metabolism both of messenger RNA (mRNA) and of small housekeeping RNAs such as small nuclear RNAs (snRNAs) are involved in the molecular mechanisms of a number of human diseases including the inherited neurodegenerative condition Spinal Muscular Atrophy (SMA). In SMA, a growing number of cellular defects have been reported, but it is far from clear which of these is most important in the development of the condition (Groen et al, 2018). Despite the clear importance of RNA metabolism, the physical organization and control of RNA processing and transport within the cell is not well understood. We have identified novel lipid-rich cellular vesicles (Prescott, et al. 2014, Thompson et al, 2018), together with alterations in the lipid profile of cellular membranes in three different SMA models. We hypothesise that the alterations seen in cellular lipids result from defects in these vesicles. This PhD studentship will use cell-culture models of SMA to investigate the composition and function of these vesicles. The vesicles contain the Survival Motor Neurons protein, mutation of which causes SMA, and the protein SmB, normally regarded as an mRNA splicing factor. We have demonstrated that these vesicles are disrupted in models of SMA. Our preliminary lipidomic analysis also shows that lipid metabolism is altered in SMA, suggesting that cellular membranes are perturbed, potentially as a result of disruption of the vesicles. We propose that these vesicles are part of the cellular RNA transport system with importance both for understanding fundamental cell biology and, in the longer term, for unraveling the complex cellular pathology of SMA with a view to developing novel therapies and biomarkers.
The project is interdisciplinary, part of a collaboration between the Sleeman group, working on cellular models of SMA and RNA metabolism, the Smith group, working on the analysis of cellular lipid metabolism and the Prescott group, experts in electron microscopy. It will involve techniques including live cell microscopy; RNA analysis; electron microscopy; lipidomics and biochemistry. The project will be based in the Biomedical Sciences Research Complex, University of St Andrews and carried out in collaboration with the School of Life Sciences, University of Dundee.
Groen EJN, Talbot K, Gillingwater TH. Advances in therapy for spinal muscular atrophy: promises and challenges. Nature reviews Neurology. 2018;14(4):214-24.
Prescott AR, Bales A, James J, Trinkle-Mulcahy L, Sleeman JE. Time-resolved quantitative proteomics implicates the core snRNP protein SmB together with SMN in neural trafficking. Journal of cell science. 2014;127(Pt 4):812-27.
Thompson LW, Morrison KD, Shirran SL, Groen EJN, Gillingwater TH, Botting CH, et al. Neurochondrin interacts with the SMN protein suggesting a novel mechanism for spinal muscular atrophy pathology. Journal of cell science. 2018;131(8).
To apply for this project, please go to this link.