RNA metabolism in health and disease: mechanisms and drug discovery
1) Molecular mechanisms of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders 2) Regulation of stress granules and paraspeckles under stress and in disease states 3) Therapeutic targeting of RNA
Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease, is a severe and inevitably fatal neuromuscular condition which currently has no cure. Disease-modifying therapies are urgently needed. To be able to find such therapies, we need better understanding of disease mechanisms, especially those applicable across different disease subtypes. Our research is focusing on the components of cellular RNA metabolism dysregulated in ALS, including lncRNA NEAT1 and RNA-binding proteins such as FUS and TDP-43.Read More
Stress granules and paraspeckles are prototypical RNP granules localised in the nucleus and cytoplasm, respectively. Recently, we found that despite their spatial separation, these two RNP granules are intimately linked. Our aim is to dissect molecular mechanisms behind paraspeckle-stress granule crosstalk.Read More
Many RNA molecules represent attractive drug targets. However, RNAs are traditionally thought to be difficult to target using small molecules. It is now increasingly appreciated that despite linearity and limited structural complexity, most RNAs contain complex 3D motifs in their structure that can serve as platforms for small molecule binding. We are exploring the possibility of using small molecules for targeting of protein-coding and non-coding RNAs to expand the boundaries of the druggable genome.Read More
Meet the team
I have been involved in biomedical research since 2008. My PhD project was aimed at development and validation of in vitro and in vivo models for testing the effects of neuroprotective compounds. In 2012, after completion of PhD studies and a short-term EMBO fellowship, I joined Prof Buchman’s laboratory at Cardiff University as a postdoctoral researcher. In 2012-2015, I was working on the molecular mechanisms of Parkinson’s disease and amyotrophic laterals sclerosis (ALS). Wishing to focus on the previously overlooked link between a specific nuclear RNA granule, the paraspeckle, and ALS pathogenesis, in 2015 I obtained funding from Medical Research Foundation (3-year fellowship). In September 2018, I started as a MND Association Senior Non-Clinical Fellow and independent group leader at the Cardiff University Medicines Discovery Institute. In September 2021, I have moved to the Sheffield Institute for Translational Neuroscience (SITraN), where I am setting up a new research group - focusing on the same areas as before but in close collaboration with SITraN's researchers. In August 2022, I started as a UKRI Future Leaders Fellow. My lab is currently supported by MRC, MND Association, BBSRC, MRC/AZ CLD and MND Scotland.
Hi I am Ved and I am a technician in TS lab. I’ve been part of the lab since April 2022 (as a student in MSc Translational Neuroscience and then as a technician). One of my projects is looking at a novel autoregulatory mechanism of FUS which is mutated protein in subset of Amyotrophic Lateral Sclerosis (ALS) cases. Another project focuses on lncRNA semi-extractability and paraspeckles. My skillset includes culturing different cell lines, performing RNA extraction, cDNA synthesis, PCR/qPCR, RNA-FISH, fluorescence microscopy and imaging. It has been a very rewarding experience working on these projects where I have learned a lot of essential lab skills and techniques.
Motivated by my fascination with clinical research from a young age, I chose to study my bachelor’s degree in Biomedical Science. During my degree I completed an NHS placement year in the Immunology lab of the Pathology department at James Cook University Hospital. My final year project focussed the role of folate depletion during pregnancy and gestation on infants’ epigenetic profile of the translocator protein gene. I completed my master’s degree in Stem Cell and Regenerative Medicine at the University of Sheffield investigating Synaptotagmin protein isoforms’ role in modulating exocytosis by G-protein coupled receptors. My most recent year of research has been in the Tsakiridis Lab in the Centre for Stem Cell Biology working on the international CONNECT project (differentiation of enteric nervous system components for a CHIP modelling system aiming to model the Parkinson’s patient nervous system for the assessment of novel therapeutics). In my current project, I am aiming to establish a reporter cell line modelling the loss of the Stathmin2 protein, a result of TDP-43 mislocalisation. Ultimately, in order to identify and optimise a small molecule modulator of splicing correction of the Stathmin-2 protein as a therapeutic approach in Amyotrophic Lateral Sclerosis.
I completed an undergraduate degree in Biomedical Science, followed by an MSc in Molecular and Cell Biology. After which, I was keen to pursue a career in academic research and joined the Campbell/Allen lab group at Sheffield Hallam university. My PhD research worked towards characterising the cellular localisation of the protein eIF2B in glial cells, with a focus on regulation by cellular stress response pathways. I then went on to complete a postdoctoral research associate position, investigating how mutations in eIF2B that are causative of the childhood neurodegenerative disease, leukoencephalopathy with vanishing white matter, impact upon the function and cellular localisation of eIF2B. I have recently joined the TS lab at SITraN as a postdoctoral research associate.
In 2019, I gained my PhD degree at the National Chung-Hsing University in Taiwan. My PhD research project focused on studying ribosomal reading-frame switch mechanisms, which is regulated by multiple translational factors such as mRNA secondary structures, charged-tRNAs availability and cellular protein factors. After graduation, I worked in the lab as a postdoctoral researcher for an international collaboration project with Dr. Guillaume Hautbergue to investigate the pathological translation mechanism in C9ORF72-ALS/FTD. It brings me to extend my RNA and translation knowledge and lab skills in the research of neurovegetative diseases. In 2021, I worked in Dr. Guillaume Hautbergue’s group as a postdoctoral researcher in ARUK project to develop compound screening assays for C9ORF72-ALS/FTD. From November 2022, I joined Dr. Tatyana Shelkovnikova’s lab for mechanistic studies of ALS-causative mutations and drugs discovery through an in vitro reconstituted-RNP complexes in MRC grant.
I studied biomedical sciences in Barcelona, where I’m from. I then moved to Scotland to pursue a master's in integrative neuroscience at Edinburgh University, where I did my project with Dr Matt Livesey performing patch clamp in iPSC-derived neurons to study neurotransmitter-gated ion channel dysregulation in ALS. I have now finished my PhD under Dr Chris Henstridge’s supervision at the University of Dundee, which centres around assessing ALS neuropathology and its association with cognitive impairment. I have experience using high-resolution imaging techniques as well as an ample histological and molecular biology. In the TS lab, I am focusing on biomolecular condensate and RBP dysfunction in MND.
My name is Ruaridh I have recently graduated from MBiolSci Molecular Biology in the School of Biosciences here at Sheffield. I have since gained a keen interest in understanding disease pathology and subsequent development of therapeutics. Outside of education I enjoy my sports where I have played rugby and competed in athletics for many years. I also enjoy hiking and climbing when the weather is behaving itself! I look forward to meeting everyone and getting started with some science!
Previous lab members: Dr Haiyan An (postdoc, 2019-2021), currently scientific officer, Swansea University Medical school. Camille Rabesahala de Meritens (technician, 2019-2021), currently PhD student, University of Geneva. Jana Kelsall (MRes student, 2020-2021). Gioana Litscher (summer student 2019), currently PhD student, University of Zurich. Jacqui Chalakova (research assistant, 2022-23), currently PDRA, King's College London. Emily Day (MSc student, 2023). Jessica Rayment (MSc student and then technician, 2022-23).
Stay in touch