Judith Sleeman
Group Highlights
Our group is based in the interdisciplinary Biomedical Sciences Research Complex.
The mammalian cell nucleus has a highly ordered structure. The detailed organisation of the nucleus and how this affects its function are not fully understood. Essential to the expression, or functioning, of genes are ‘transcription’ of the DNA instructions into a messenger RNA (mRNA) intermediate and ‘translation’ of this into the protein ‘product’ of the gene. Almost all mammalian genes contain introns, which are sequences represented in the DNA but not in the protein. These must be removed, or ‘spliced’, from the mRNA message before it can be translated. The accuracy of mRNA splicing is essential for correct gene expression.
snRNPs (small nuclear ribonucleoproteins) are essential splicing factors and show a complex pattern of distribution within the nucleus. They localise to a number of nuclear domains including speckles and Cajal bodies. The formation of snRNPs is a complex process. Early steps occur outside the nucleus in the cytoplasm, and require a protein called Survival of Motor Neurons (SMN).
Insufficient expression of SMN is responsible for the inherited neurodegenerative disease, spinal muscular atrophy (SMA). SMN is also found in the nucleus where it concentrates, along with snRNPs, in Cajal bodies. It is not clear how the loss of SMN protein leads to the disease. All cells need to splice their RNA correctly, but SMA specifically affects motor neurons. It is also possible that SMN is needed to transport mature mRNAs within cells and that this function is particularly important in motor neurons becuase of their immense length.
We study the maturation of snRNP splicing factors and the transport of mature mRNA, with a particular emphasis on their dynamics within the nucleus and differences between neural and non-neural cell types that may be significant for SMA.
For Spinal Muscular Atrophy information and support, please click here.
Our group website: https://sleeman.wp.st-andrews.ac.uk/
Research
Our recent research has been expanding from its original focus on nuclear dynamics and splicing snRNP maturation to look at broader connections between RNA metabolism and inherited disease. We are predominantly interested in Spinal Muscular Atrophy, and have also published data on the dynamics of pathological nuclear RNA foci seen in Myotonic Dystrophy Type 1.
We have pioneered the use of a combination of quantitative proteomics and timed expression of GFP-tagged proteins to dissect stages of splicing snRNP maturation. This has led us to identify a novel cytoplasmic structure implicated in SMA pathology and provided insight into the complexity of interactions between SMN and splicing factors of relevance to SMA.
Group Members
Publications
Articles
Condensation properties of stress granules and processing bodies are compromised in myotonic dystrophy type 1
Gulyurtlu, S., Magon, M. S., Guest, P. N., Papavasiliou, P. P., Morrison, K., Prescott, A. & Sleeman, J. E., 2 Aug 2022, In: Disease Models & Mechanisms. 15, 7, dmm049294.
Research output: Contribution to journal › Article › peer-review
The ‘most expensive drug in the world’, how it works and the devastating disease it treats
Sleeman, J. E., 19 Jul 2021, The Conversation.
Research output: Contribution to specialist publication › Article
Neurochondrin interacts with the SMN protein suggesting a novel mechanism for Spinal Muscular Atrophy pathology
Thompson, L. W., Morrison, K. D., Shirran, S. L., Groen, E. J. N., Gillingwater, T. H., Botting, C. H. & Sleeman, J. E., 17 Apr 2018, In: Journal of Cell Science. 131, 8, 18 p., jcs211482.
Research output: Contribution to journal › Article › peer-review
The Cajal body and the nucleolus: “in a relationship” or “it's complicated”?
Trinkle-Mulcahy, L. & Sleeman, J. E., 2017, In: RNA Biology. 14, 6, p. 739-751
Research output: Contribution to journal › Review article › peer-review
Nuclear bodies: new insights into assembly/dynamics and disease relevance
Sleeman, J. E. & Trinkle-Mulcahy, L., Jun 2014, In: Current Opinion in Cell Biology. 28, p. 76-83 8 p.
Research output: Contribution to journal › Article › peer-review
Time-resolved quantitative proteomics implicates the core snRNP protein SmB together with SMN in neural trafficking
Prescott, A. R., Bales, A., James, J., Trinkle-Mulcahy, L. & Sleeman, J. E., 14 Feb 2014, In: Journal of Cell Science. 127, 4, p. 812-827 15 p.
Research output: Contribution to journal › Article › peer-review
Transcriptionally correlated subcellular dynamics of MBNL1 during lens development and their implication for the molecular pathology of myotonic dystrophy type 1
Coleman, S., Prescott, A. R. & Sleeman, J. E., 1 Mar 2014, In: Biochemical Journal. 458, 2, p. 267-280 13 p.
Research output: Contribution to journal › Article › peer-review
Small nuclear RNAs and mRNAs: linking RNA processing and transport to spinal muscular atrophy
Sleeman, J., Aug 2013, In: Biochemical Society Transactions. 41, 4, p. 871-875 5 p.
Research output: Contribution to journal › Article › peer-review
Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy
Clelland, A. K., Bales, A. B. E. & Sleeman, J. E., 1 Jun 2012, In: Journal of Cell Science. 125, 11, p. 2626-2637 12 p.
Research output: Contribution to journal › Article › peer-review
The SMN protein is a key regulator of nuclear architecture in differentiating neuroblastoma cells
Clelland, A. K., Kinnear, N. P., Oram, L., Burza, J. & Sleeman, J. E., Nov 2009, In: Traffic. 10, 11, p. 1585-1598 14 p.
Research output: Contribution to journal › Article › peer-review
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