EMC-2024-6_Sleeman: Analysis of the roles of protein arginine methylation in motor neuron disease using quantitative proteomics


   Centre for Clinical Brain Sciences

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  Dr Judith Sleeman, Dr Sally Shirran  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

THIS PROJECT WILL BE BASED AT THE UNIVERSITY OF ST ANDREWS

This project is on offer as part of the studentship scheme of the Euan MacDonald Centre for Motor Neuron Disease Research. The Euan MacDonald Centre is a multi-disciplinary network of MND researchers across Scotland. A choice of six projects is on offer now for a start date in Autumn 2024, at the University of Edinburgh, St Andrews or Dundee. For more information see www.euanmacdonaldcentre.org/phd-scheme. Euan MacDonald Centre students join our network of >200 MND researchers across Scotland and will have the opportunity to meet people living with MND, participate in academic and public engagement events led by the Centre. To view all the projects offered under this scheme please search for reference numbers EMC-2024-1 to EMC-2024-6.

Arginine methylation is a post-translational modification (PTM) that is rapidly gaining attention in the fields of neurodegeneration and fundamental cell biology. RNA binding proteins (RBPs) including TDP43 and FUS, implicated in Amyotrophic Lateral sclerosis (ALS) as well as Sm proteins and SMN, implicated in Spinal Muscular Atrophy (SMA) are modified by arginine methylation. The methylation influences both their sub-cellular distribution, where defects can result in cytoplasmic accumulations similar to those seen in neurodegenerative conditions; and their binding characteristics, influencing which other proteins and RNAs they can interact with. Protein arginine methylation can be influenced using drugs and may prove to be an appropriate target for therapy development.

We have recently generated two sets of neuroblastoma cell lines in which we can 1) manipulate the expression of one of the enzymes responsible for arginine methylation of proteins and 2) express tagged versions of wild-type FUS or a mutant of FUS associated with ALS. This project will exploit these cell lines in a variety of different quantitative (SILAC) proteomic screens and structural and functional assays to address a number of linked questions about the following:

A) the influence of protein arginine methylation on proteins implicated in motor neuron disease pathology and on the internal cellular structure and capacity for differentiation of neuroblastoma cells and

B) the effect of expression of mutant FUS on the arginine methylation of endogenous proteins that normally carry this modification.

Suitable first degree subjects: Molecular biology, cell biology, biochemistry, bioinformatics. Essential and/or desirable skills and experience: Mammalian cell culture, microscopy, protein analysis, bioinformatics. 

Biological Sciences (4) Medicine (26)

Funding Notes

The studentship comprises 42 months (3.5 years) stipend payments at the standard UKRI rate, tuition fees and an allowance of £10K per year for three years for consumables and travel. The studentship is open to applicants worldwide. Students will register for the most appropriate degree programme at the University where the project is being offered. It is the applicants’ responsibility to ensure they meet the eligibility requirements for postgraduate study at their chosen University, in terms of academic achievements and English language proficiency.

References

Gill AL, Premasiri AS, Vieira FG. (2021). Hypothesis and Theory: Roles of Arginine Methylation in C9orf72-Mediated ALS and FTD. Front Cell Neurosci. 2021 Mar 23;15:633668. doi: 10.3389/fncel.2021.633668. eCollection
Gulyurtlu S, Magon MS, Guest P, Papavasiliou PP, Morrison KD, Prescott AR, Sleeman JE. (2022). Condensation properties of stress granules and processing bodies are compromised in myotonic dystrophy type 1. Dis Model Mech. 2022 Jul 1;15(7):dmm049294. doi: 10.1242/dmm.049294. Epub 2022 Aug 2. PMID: 35642886
Prescott AR, Bales A, James J, Trinkle-Mulcahy L, Sleeman JE. (2014). Time-resolved quantitative proteomics implicates the core snRNP protein SmB together with SMN in neural trafficking. J Cell Sci. 2014 Feb 15;127(Pt 4):812-27. doi: 10.1242/jcs.137703. Epub 2013 Dec 19. PMID: 24357717

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