Birkbeck, University of London Featured PhD Programmes
Norwich Research Park Featured PhD Programmes
Norwich Research Park Featured PhD Programmes
University of Kent Featured PhD Programmes
European Molecular Biology Laboratory (Heidelberg) Featured PhD Programmes

Impaired stress response as a pathological mechanism in Myotonic Dystrophy Type 1 and related degenerative conditions

  • Full or part time
    Dr J Sleeman
  • Application Deadline
    Sunday, December 01, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Myotonic Dystrophy Type1 (DM1) is an incurable inherited multi-system disease that results in numerous symptoms including early cataract development, which can be the first sign of the disease. The eye lens grows continuously throughout life by differentiation of a stem cell pool in the lens epithelium into optically clear fibre cells. This involves clearance of cellular organelles including the nucleus. The process is not well understood, but transcriptional shut-down precedes the loss of the nucleus (1) and autophagy, a normal cellular mechanism for degradation of cellular components, is essential for lens development (reviewed in 2). DM1 is caused by an expanded CUG triplet repeat in the DMPK1 (Dystrophia Myotonica Protein Kinase) gene. This results in accumulation of faulty mRNA in nuclear foci (CUGexp foci). It is not clear how these foci lead to the various symptoms seen, but similar nuclear RNA foci are also formed in some familial forms of ALS (Amyotrophic Lateral Sclerosis, motor neuron disease), suggesting that the underlying pathological consequences of these RNA foci may be relevant for understanding a number of degenerative conditions. Two anatagonistic pre-mRNA splicing factors, MBNL1 (Muscleblind-like1) and CUGBP1 (CUG Binding Protein1) are implicated in DM1. MBNL1 accumulates in CUGexp foci and it is thought this may compromise its function in splicing, while CUGBP1 activity is up-regulated in DM1. We have access to human lens epithelial (HLE) cell lines from DM1 patients in which we have documented the presence of CUGexp foci (3) and the accumulation of MBNL1 in them. However, only ~0.1% of total cellular MBNL1 is found in CUGexp foci, suggesting that defective splicing is unlikely to be the underlying basis of DM1-associated cataract. In addition to roles in pre-mRNA splicing, MBNL1 and CUGBP1 have also been implicated in cytoplasmic regulation of mRNA (reviewed in 4). We have recently identified both MBNL1 and CUGBP1 in cytoplasmic stress granules (SGs) (previously reported for MBNL1), and in P-bodies (our novel observation) (Fig.1). P-bodies are found in most cells, while SGs usually occur only during cellular stress. The structures are closely related, both implicated in cytoplasmic mRNA regulation. Under conditions of physiological stress, we show delayed SG formation in cells containing CUGexp foci (lens epithelial cells from DM1 patients and our newly-established inducible HeLa cell model), suggesting that disruption of cellular mRNA regulation may occur in DM1. In yeast, the clearance of SGs involves autophagy, the same mechanism that is important in clearing cellular structures during lens differentiation (5). The cells of the eye lens epithelium are subject to an unusually high level of environmental stress (reviewed in 6). We hypothesise that DM1 patient-derived cells show altered responses to stress caused by MBNL1/CUGBP1 disruption and that this plays a role in the development of symptoms including cataract.
This PhD project will use combine cell biology and advanced microscopy approaches with quantitative proteomics and bioinformatics to investigate the role of stress responses in DM1 with the potential to expand the work further into cell culture models of motor neuron disease. Training will be given in all of these areas and the University of St Andrews also runs a world-class programme of training workshops and activities designed specifically for research postgraduate students.
Informal enquiries are strongly encouraged and should be made by email to Dr Judith Sleeman.

Funding Notes

Eligibility requirements: Upper second-class degree in Biology or a related area.
Funding: Fees and stipend is provided for 3.5 years.

References

1) Gribbon, C., Dahm, R., Prescott, A. R. and Quinlan, R. A. (2002). Association of the nuclear matrix component NuMA with the Cajal body and nuclear speckle compartments during transitions in transcriptional activity in lens cell differentiation. Eur J Cell Biol 81, 557-66.
2) Morishita, H. and Mizushima, N. (2016). Autophagy in the lens. Exp Eye Res 144, 22-8.
3) Coleman, S. M., Prescott, A. R. and Sleeman, J. E. (2014). Transcriptionally correlated subcellular dynamics of MBNL1 during lens development and their implication for the molecular pathology of myotonic dystrophy type 1. Biochem J 458, 267-80.
4) Brinegar, A. E. and Cooper, T. A. (2016). Roles for RNA-binding proteins in development and disease. Brain Res 1647, 1-8.
5) Buchan, J. R., Kolaitis, R. M., Taylor, J. P. and Parker, R. (2013). Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153, 1461-74.
6) Hejtmancik, J. F., Riazuddin, S. A., McGreal, R., Liu, W., Cvekl, A. and Shiels, A. (2015). Lens Biology and Biochemistry. Prog Mol Biol Transl Sci 134, 169-201.

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)

Click here to see the results for all UK universities

Email Now

Insert previous message below for editing? 
You haven’t included a message. Providing a specific message means universities will take your enquiry more seriously and helps them provide the information you need.
Why not add a message here
* required field
Send a copy to me for my own records.

Your enquiry has been emailed successfully





FindAPhD. Copyright 2005-2019
All rights reserved.