Tatyana Shelkovnikova Lab

RNA metabolism in health and disease: mechanisms and drug discovery

RESEARCH

We have several fundamental and translational projects falling into three main themes

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

Molecular mechanisms of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders

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.

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Regulation of stress granules and paraspeckles under stress and in disease states

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.

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Therapeutic targeting of RNA

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.

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Who are we?

Meet the team

Dr Tatyana Shelkovnikova

Group Leader

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.

Vedanth Kumar

Technician

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.

Brittany Ellis

PhD student

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.

Rachel Hodgson

Postdoctoral researcher

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.

Wan-Ping (Cara) Huang

Postdoctoral researcher

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.

Anna Avila Sanchez

Postdoctoral researcher

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.

Ruaridh Lang

PhD student

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!

Alumni

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).

Our Supporters

Look into those who make it possible

Funding image
We are currently supported by:

  • UKRI FLF
Fellowship "RNP complexes in health and disease and their therapeutic targeting" (2022-2026)

  • Motor Neurone Disease Association
Senior Non-Clinical Fellowship (converted into a research grant): “Long non-coding RNA NEAT1 in motor neurone physiology and pathophysiology” (2018-2023)

PhD studentship: "NEAT1 isoforms in the regulation of cellular glucose metabolism downstream TDP-43 dysfunction in ALS" (2023-2027)

  • MRC
Research grant: "Mechanistic studies of ALS-causative mutations and RNP-focussed drug discovery using in vitro reconstitution of RNP complexes" (2022-2025)

  • MND Scotland
PhD Studentship: "Small molecule modulators of stathmin-2 splicing as a novel ALS therapy"(2022-2025)

  • BBSRC
Research grant: “Understanding the crosstalk between spatially separated RNP granules during cellular stress responses” (2022-2024)

  • MRC/AZ Centre for Lead Discovery award for the identification of small molecules modulators of NEAT1_2/paraspeckles (co-I, with Cardiff)

Previous funding:
  • Medical Research Foundation
MRF fellowship: “Dissecting the role of the paraspeckle in amyotrophic lateral sclerosis” (2015-2018)
  • Academy of Medical Sciences
AMS Springboard Award: “Developing tools to monitor expression of lncRNA NEAT1 isoforms for basic research and drug discovery” (2019-2021)
  • ISSF Wellcome Trust
ISSF Translational Kickstart Award “Identification of chemotypes selectively binding to a structured motif of lncRNA NEAT1 as templates for novel drugs” (2019-2021)
  • Welsh Government 
Sêr Cymru III – Tackling COVID-19 grant (2020-2021)
29 January 2024
Rachel presented on opto-DPRs at a departmental seminar - this work should be preprinted soon.

25 January 2024
New PhD is advertised in the lab (optogenetics), with deadline on 13th February: https://www.findaphd.com/phds/project/deciphering-the-c9orf72-dpr-aggregation-pathology-in-neurodegeneration-using-optogenetic-and-in-vitro-analyses-of-modifiers/?p168134 

10 December 2023
Rachel and TS attended and gave oral talks at 34th Symposium on ALS/MND in Basel (6-8 Dec). It was Rachel's first MND symposium - hope one of many!


20 October 2023
TS (main supervisor), Sean Sweeney (York) and John Atack had their MRC DiMeN PhD project selected to be advertised. If you are interested to apply for a PhD in TS lab, get in touch - link to the project.

9 October 2023
1st paraspeckle symposium was a success!! Photos are in the gallery. Looking to repeat in 2024 in Australia.

1 October 2023
We are delighted to welcome Ruaridh - new PhD student in the lab working on a MNDA-funded project (joint with Scott Allen).

19 September 2023
TS (main supervisor) and Mark Dickman (Engineering, co-supervisor) had their BBSRC DTP PhD project selected. If you are interested to apply for a PhD in TS lab, get in touch - link to project

15 September 2023
Guillaume Haurbergue's paper on PGC1a as an RNA export adapter has been published in Nat Comms. TS is really happy to have contributed to this really nice story! https://pubmed.ncbi.nlm.nih.gov/37679383/ 

6-8 September 2023
Cara and TS attended the 1st TDP-43 conference in Trieste and presented some of the most recent unpublished data on the role of TDP-43 in paraspeckles (talk and poster). 3 days of TDP-43 biology - what can be better?..

8 September 2023

Brittany has passed her confirmation review with no corrections!

25 August 2023
Emily presented on her MSc thesis. TS was marking the other session so could not attend but everyone said she did fantastic. Congratulations on passing the final bit of your assessment Emily!

19th August 2023
Ved and Anna took part in the Soak a Scientist challenge. Not only got they soaked but Ved also baked for the event. Photos to follow in the gallery.

10th August 2023
Department sponsored trip to Yorkshire Sculpture park! Lots of gaming and sunshine. TS was gutted because she could not go :(

July 2023
It's time to say goodbye to Jess who is off to travelling the world. We wish you all the luck in this new adventure (and please be careful whilst swimming to Cuba - may be take a couple of lessons first!). The image from Jess' mug - also in the gallery! A trip to the Notty house was essential - Jess requested to have one last local pie .. sounded like she'll miss the pies more than us..


17 July 2023
Jess and Cara presenting at the Medical Research School Day 2023:

July 12-14 2023
Ved, Jess, Brittany and Anna attended ENCALS - the first (I am sure of many!) ENCALS for them. Lots of discussions by the posters, fantastic time.

July 2023
TS and Archa Fox (UWA) are organising the first international conference on Paraspeckle biology!!! 8th October 2023, Surrey (satellite to RNA granules). Get in touch if you think your research is relevant: Conference contact/enquiries: paraspeckle.symposium@gmail.com. Rachel and Cara are conference technical committee.

5 July 2023
TS gave an invited talk about her fellowship journey at the Fellowship Day 2023 at the Department of Neuroscience.

01 July 2023
The lab welcomed a new postdoc - Anna Sanchez Avila, who was previously with Chris Henstridge in Dundee and just finished her PhD. Photos to follow!

June 2023
Brittany attended MND EnCouRage UK 2023 and talked about her project to the audience that included patients living with the disease and their carers.

April 2023
Jess, Ved and Brittany had their posters accepted to Encals 2023 in Barcelona so the lab will be well-represented at the conference.

29 March 2023
We are delighted to receive BBSRC Australia partnering award with Archa Fox at UWA. As part of this award, we will organise the 1st international Paraspeckle Biology symposium focused solely on paraspeckles. More detail to follow!

8 March 2023
We have a PhD studentship advertised on findPhD - PTMs in regulation of RNP granules (withMark Dickman and Caroline Evans), international candidates can apply (deadline 5 Apri) - use this link.

27 February 2023
Jess delivered a fantastic presentation at the internal SITraN seminar series. Her talk title was: Using optogenetic tools for modeling neurodegenerative disease pathology. Very well done!

31 January 2023
We bid a sad farewell to Jacqui - who secured a postdoc at Centre for Developmental Neurobiology, King's College London. To celebrate this (not Jacqui's departure but her new exciting appointment), a visit to Nottingham House was paid and a lot of pies were consumed.. Good luck with your new adventure Jacqui! Missing you..
January 2022
We are recruiting! The lab is looking for a postdoctoral researcher with a bioinformatics background, to join the UKRI FLF-funded project. The position is full time and 3 years in duration. If interested, please contact TS directly to discuss by email: t.shelkovnikova@sheffield.ac.uk 


20 January 2022
Jacqui and Rachel's work on super-resolution imaging of paraspeckles in cell models of ALS was presented at the SM@SH Single Molecule showcasing event in Sheffield by Rachel.

15 December 2022
Christmas dinner -Hautbergue and TS labs at the Lescar!

13 December 2022
RNA granules 2023 conference Register interest page is now live! https://www.biochemistry.org/events-and-training/events-calendar/rna-granules-2023/

Together with colleagues from Surrey, Sheffield and Manchester and support from the Biochemical Society, we are organising the international conference “RNA Granules 2023: from basic biology, functions to drug discovery", to be held in Surrey (UK), 9-11th October 2023.

The previous RNA granules conferences held in 2014 and 2017 in Canada and Germany were a success (the 2020 Vancouver meeting was cancelled due to COVID). The 2023 conference sessions will cover several themes, including Biocondensates Biogenesis and Dynamics, Biocondensates in Neurological Disorders, Cancer and Infections, Innovation and Methodological Advances, Therapeutics, Physico-Chemical properties of Phase Separation. Roy Parker is a confirmed keynote speaker. More information is to follow in early 2023 - stay tuned by signing up to the conference updates using the link above!

12 November 2022
TS's profile on ResearchGate achieved 10,000 reads!

November 2022
The lab welcomed 2 new postdocs, Cara and Rachel - welcome to the team!

October 2022
TS's first MSc students at Sheffield, Ved and Jess - who are have joined as technicians now - had their graduation ceremony! So pleased and proud for them!!

October 2022
The lab welcomed a PhD student, Brittany, and three technicians, Ved, Jacqui and Jess - warm welcome!

29 September 2022
Our review on the use of OTIs as precision gene editors in neurodegenerative diseases led by Ben Bax (Cardiff) has been published: https://www.mdpi.com/1422-0067/23/19/11541

13 September 2022
Our collaborative MRC/AZ CLD project (with Prof John Atack at Cardiff MDI) was awarded! We will be granted access to the AZ small molecule collection to find NEAT1/paraspeckle targeting molecules.

26 August 2022
Our Nucleic Acids Research paper on therapeutic targeting of NEAT1/paraspeckles has been accepted!! See here (and soon in the paper section).

5 April 2022
TS and Guillaume Hautbergue were awarded a 3-year MRC research grant to establish a biochemical assay for analysis of ALS-linked RNP complexes, suitable for screening of small molecules. The recruitment on this grant (3-year postdoctoral position, full time) to begin soon (will be posted here).

4 February 2022
TS and Kurt De Vos have been awarded a PhD studentship to identify drugs that modulate STMN2 splicing, by MND Scotland. Needless to say that we are honored and excited to be selected within this completive scheme. The project is currently advertised on Findaphd, until 6th May:
https://www.findaphd.com/phds/project/small-molecule-modulators-of-alternative-splicing-as-a-novel-therapy-for-amyotrophic-lateral-sclerosis-als/?p143014

6 September 2021
Lab has moved to SITraN, Sheffield. Exciting times!!

5 May 2021
Tatyana has been awarded a BBSRC grant, together with Nicolas Locker from Surrey, to look into the molecular mechanisms of stress granule - paraspeckle crosstalk.

16 March 2021
MND Research blog about our work was published, check it here: https://mndresearch.blog/2021/03/16/flexible-molecules-and-droplets-researching-and-targeting-rna-protein-complexes-in-mnd/

02 March 2021
Our study on the analysis of FUS aggregate composition is now available as a preprint: https://www.biorxiv.org/content/10.1101/2021.03.02.433611v1 

11 January 2021
The paper with our collaborators in Tokyo, Nevada and Moscow has been accepted for publication at the RNA Biology journal.

08 December 2020
Tatyana is this year's winner of the ENCALS Young Investigator Award!

07 October 2020
The lab has received a grant from the Welsh Government for a COVID-19 drug discovery project. Can't wait to start it!

04 May 2020
Our paper on neurological phenotypes in Neat1 knockout mice (previously available as preprint), with Haiyan, Camille and Tatyana as authors, has been accepted for publication in the Translational Psychiatry journal.

30 April 2020
Our paper on the effect of FUS frameshift mutations, with Haiyan, Camille and Tatyana as authors, has been accepted for publication in the Molecular Brain journal.

12 February 2020
Tatyana presented at CU School of Dentistry seminar: “Therapeutic targeting of RNA – expanding the boundaries of the druggable genome?”

14 January 2020
Tatyana invited to give a talk on paraspeckle regulation by stress granules at the RNA UK 2020 meeting
https://www.rnauk2020.org/

21 November 2019
Invited commentary on our J Cell Biol paper was published in Cell Stress
check free text: https://www.cell-stress.com/researcharticles/2019a-an-microbial-cell/

23 October 2019
Haiyan had her PhD viva – only minor corrections! Congratulations!!!

23 September 2019
The very first lab’s preprint, with Haiyan, Camille and Tatyana as authors, published on bioRxiv: https://www.biorxiv.org/content/10.1101/773333v1

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  • SITraN, The University of Sheffield, 385a Glossop Road, Broomhall, Sheffield S10 2HQ, UK

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