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Quantitative interactomics to identify cellular pathways affected in Spinal Muscular Atrophy

  • Full or part time
    Dr J Sleeman
  • Application Deadline
    Friday, April 05, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

The Sleeman group is interested in the molecular and cellular mechanisms that lead to symptoms in the inherited motor neurone disease, Spinal Muscular Atrophy (SMA). It is increasingly apparent that there are common mechanisms at play in SMA and Amyotrophic Lateral Sclerosis (ALS or classical Motor Neurone Disease). We use a range of interdisciplinary approaches, including cell biology, live cell microscopy, quantitative proteomics and electrophysiology to answer our research questions. This is achieved through collaboration with experts here in St Andrews and at the Universities of Edinburgh and Aberdeen.

Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative condition resulting from production of insufficient amounts of the Survival Motor Neurones (SMN) protein due to mutation or deletion of the SMN1 gene. There is an increasing appreciation that SMA is not a classical motor neurone disease, but rather a systemic disease in which motor neurones (MNs) are most vulnerable or in which defects in MNs are most clinically relevant. The first therapy for SMA, Nusinersen/Spinraza, increases production of SMN in the central nervous system but not in other tissues or organs.

The SMN protein is essential in all cells, with many roles including assembly of snRNP splicing factors, mRNA transport and vesicular trafficking. It is unclear which of these roles underlie the cellular pathology of SMA in MNs, or whether different pathways are important in different cell types. A modifier gene, SMN2, can make a small amount of full-length SMN. However, most transcripts from SMN2 are mis-spliced and produce a truncated protein, SMN∆7, which cannot fully substitute for full-length SMN. We will adopt quantitative proteomic approaches to identify differences between the cellular proteins interacting with FL-SMN and those interacting with SMN∆7. Our preliminary data suggest that there are some proteins that interact only with SMN∆7, as well as some that interact only with FL-SMN. This information will be used to develop testable hypotheses concerning the molecular defects resulting from insufficient levels of FL-SMN in MNs and other cell types, with a view to the rational design of novel therapies for SMA.

Funding Notes

This studentship is part of the prestigious SPRINT-MND/MS PhD Programme co-ordinated by the University of Edinburgh:
View Website

With the exception of this studentship (see also project View Website), the programme is closed to applicants for 2019 entry.
Please get in touch with Dr Judith Sleeman by email () if you are interested in this studentship.

References

L Thompson, K Morrison, E. Groen, T. Gillingwater, S Shirran, C Botting, J Sleeman (2018) Neurochondrin interacts with the SMN protein suggesting a novel mechanism for Spinal Muscular Atrophy pathology. J. Cell Sci. 131(8). doi:10.1242/jcs.211482.

Time-resolved quantitative proteomics implicates the core snRNP protein, SmB, in neural trafficking. Alan R Prescott, Alexandra Bales, John James, Laura Trinkle-Mulcahy and Judith E. Sleeman. (2014) J Cell Sci. 127:812-827.

Maxwell, GK., Szunyogova, E. Shorrock, H.K., Gillingwater, TH. & Parson, SH. (2018). 'Developmental and Degenerative Cardiac Defects in the Taiwanese Mouse Model of Severe Spinal Muscular Atrophy'. Journal of Anatomy, vol. 232, no. 6, pp. 965-978.

Thomson, AK., Somers, E., Powis, RA., Shorrock, HK., Murphy, K., Swoboda, KJ., Gillingwater, TH. & Parson, SH. (2017). 'Survival of motor neurone protein is required for normal postnatal development of the spleen'. Journal of Anatomy, vol. 230, no. 2, pp. 337-346.

How good is research at University of St Andrews in Biological Sciences?

FTE Category A staff submitted: 50.45

Research output data provided by the Research Excellence Framework (REF)

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