Dr Tatyana Shelkovnikova

PhD

Department of Neuroscience

UKRI Future Leaders Fellow (Senior Research Fellow)

t.shelkovnikova@sheffield.ac.uk
+44 114 22 22270

Sheffield Institute for Translational Neuroscience (SITraN)

Full contact details

Dr Tatyana Shelkovnikova
Department of Neuroscience
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
Sheffield
S10 2HQ

Profile: After graduating with an MSc degree in Genetics in 2008, I pursued a PhD in Biochemistry which I completed in 2012. During my PhD training, supported by an EMBO fellowship, I contributed to the generation and characterisation of a unique mouse model of a fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS); report on this mouse model published in J Biol Chem was selected as Paper of the Year. I continued to develop this stream of research during my postdoctoral training at Cardiff University (Prof Buchman’s lab), where I spearheaded a number of projects focussing on (dys)metabolism of ribonucleoprotein (RNP) granules in ALS. In 2015, these studies were supported by a 3-year fellowship from the Medical Research Foundation. In 2018, I was awarded a 4-year senior non-clinical fellowship from the MND Association and started my own group at the Medicines Discovery Institute, a newly established Cardiff University’s translational unit. During my time at the MDI, my research was supported by AMS Springboard award, the ISSF Translational Kick-Start award and funding from Welsh Government. I am the recipient of the ENCALS Young Investigator award 2020. In September 2021, I moved to SITraN, University of Sheffield, to continue studies into the molecular pathogenesis of ALS and related disorders within a world-leading centre for neurodegenerative disease research. In May 2022, I was awarded the UKRI Future Leaders Fellowship to establish a research programme entitled “RNA-protein complexes in health and disease and their therapeutic targeting”. The group is also currently funded by MNDA, BBSRC, MRC and MND Scotland.

Research interests

My group aims to provide insights into molecular underpinnings of RNP granule biology and their connection to human disease. Our overarching goals are:

to establish how altered composition and metabolism of the two types of RNP granules, stress granules and paraspeckles, contribute to the pathogenesis of ALS and frontotemporal dementia (FTD);
to discover and validate druggable targets for these devastating and currently incurable conditions;
to identify novel chemical probes for modulation of RNAs and RNP complexes.

Publications

Journal articles

Bax BD, Sutormin D, McDonald NQ, Burley GA & Shelkovnikova T (2022) Oligonucleotide-recognizing topoisomerase inhibitors (OTIs): precision gene editors for neurodegenerative diseases?. International Journal of Molecular Sciences, 23(19).
Cooper‐Knock J, Julian TH, Feneberg E, Highley JR, Sidra M, Turner MR, Talbot K, Ansorge O, Allen SP, Moll T , Shelkovnikova T et al (2022) Atypical TDP-43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP. Brain Pathology. View this article in WRRO
An H, Litscher G, Watanabe N, Wei W, Hashimoto T, Iwatsubo T, Buchman VL & Shelkovnikova TA (2022) ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity.. Neurobiol Dis, 162, 105585.
Matsukawa K, Kukharsky MS, Park S-K, Park S, Watanabe N, Iwatsubo T, Hashimoto T, Liebman SW & Shelkovnikova TA (2021) Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy. RNA Biology, 18(11), 1546-1554.
Kukharsky MS, Ninkina NN, An H, Telezhkin V, Wei W, Meritens CRD, Cooper-Knock J, Nakagawa S, Hirose T, Buchman VL & Shelkovnikova TA (2020) Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice. Translational Psychiatry, 10(1).
An H, Rabesahala de Meritens C, Buchman VL & Shelkovnikova TA (2020) Frameshift peptides alter the properties of truncated FUS proteins in ALS-FUS. Molecular Brain, 13(1).
An H, Tan JT & Shelkovnikova TA (2019) Stress granules regulate stress-induced paraspeckle assembly. Journal of Cell Biology, 218(12), 4127-4140.
Shelkovnikova TA, An H, Skelt L, Tregoning JS, Humphreys IR & Buchman VL (2019) Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis. Cell Reports, 29(13), 4496-4508.e4.
An H, Skelt L, Notaro A, Highley JR, Fox AH, La Bella V, Buchman VL & Shelkovnikova TA (2019) ALS-linked FUS mutations confer loss and gain of function in the nucleus by promoting excessive formation of dysfunctional paraspeckles. Acta Neuropathologica Communications, 7. View this article in WRRO
An H, Williams NG & Shelkovnikova TA (2018) NEAT1 and paraspeckles in neurodegenerative diseases: A missing lnc found?. Non-coding RNA Research, 3(4), 243-252.
Shelkovnikova TA, Kukharsky MS, An H, Dimasi P, Alexeeva S, Shabir O, Heath PR & Buchman VL (2018) Protective paraspeckle hyper-assembly downstream of TDP-43 loss of function in amyotrophic lateral sclerosis. Molecular Neurodegeneration, 13(1). View this article in WRRO
Shelkovnikova TA, Dimasi P, Kukharsky MS, An H, Quintiero A, Schirmer C, Buée L, Galas M-C & Buchman VL (2017) Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly. Cell Death & Disease, 8(5), e2788-e2788.
Dimasi P, Quintiero A, Shelkovnikova TA & Buchman VL (2017) Modulation of p-eIF2α cellular levels and stress granule assembly/disassembly by trehalose. Scientific Reports, 7(1).
Scekic‐Zahirovic J, Sendscheid O, El Oussini H, Jambeau M, Sun Y, Mersmann S, Wagner M, Dieterlé S, Sinniger J, Dirrig‐Grosch S , Drenner K et al (2016) Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. The EMBO Journal, 35(10), 1077-1097.
Ninkina N, Connor-Robson N, Ustyugov AA, Tarasova TV, Shelkovnikova TA & Buchman VL (2015) A novel resource for studying function and dysfunction of α-synuclein: mouse lines for modulation of endogenous Snca gene expression. Scientific Reports, 5(1).
Kukharsky MS, Quintiero A, Matsumoto T, Matsukawa K, An H, Hashimoto T, Iwatsubo T, Buchman VL & Shelkovnikova TA (2015) Calcium-responsive transactivator (CREST) protein shares a set of structural and functional traits with other proteins associated with amyotrophic lateral sclerosis. Molecular Neurodegeneration, 10(1).
Peters OM, Shelkovnikova T, Highley JR, Cooper‐Knock J, Hortobágyi T, Troakes C, Ninkina N & Buchman VL (2015) Gamma‐synuclein pathology in amyotrophic lateral sclerosis. Annals of Clinical and Translational Neurology, 2(1), 29-37. View this article in WRRO
Robinson HK, Deykin AV, Bronovitsky EV, Ovchinnikov RK, Ustyugov AA, Shelkovnikova TA, Kukharsky MS, Ermolkevich TG, Goldman IL, Sadchikova ER , Kovrazhkina EA et al (2015) Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition motif. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 16(5-6), 402-409.
Shelkovnikova TA, Robinson HK, Southcombe JA, Ninkina N & Buchman VL (2014) Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent and RNA-independent mechanisms. Human Molecular Genetics, 23(19), 5211-5226.
Shelkovnikova TA, Robinson HK, Troakes C, Ninkina N & Buchman VL (2014) Compromised paraspeckle formation as a pathogenic factor in FUSopathies. Human Molecular Genetics, 23(9), 2298-2312.
Shelkovnikova TA (2013) Modelling FUSopathies: focus on protein aggregation. Biochemical Society Transactions, 41(6), 1613-1617.
Shelkovnikova TA, Robinson HK, Connor-Robson N & Buchman VL (2013) Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm. Cell Cycle, 12(19), 3383-3391.
Shelkovnikova TA, Peters OM, Deykin AV, Connor-Robson N, Robinson H, Ustyugov AA, Bachurin SO, Ermolkevich TG, Goldman IL, Sadchikova ER , Kovrazhkina EA et al (2013) Fused in Sarcoma (FUS) Protein Lacking Nuclear Localization Signal (NLS) and Major RNA Binding Motifs Triggers Proteinopathy and Severe Motor Phenotype in Transgenic Mice. Journal of Biological Chemistry, 288(35), 25266-25274.
Peters OM, Shelkovnikova T, Tarasova T, Springe S, Kukharsky MS, Smith GA, Brooks S, Kozin SA, Kotelevtsev Y, Bachurin SO , Ninkina N et al (2013) Chronic Administration of Dimebon does not Ameliorate Amyloid-β Pathology in 5xFAD Transgenic Mice. Journal of Alzheimer's Disease, 36(3), 589-596.
Peters OM, Millership S, Shelkovnikova TA, Soto I, Keeling L, Hann A, Marsh-Armstrong N, Buchman VL & Ninkina N (2012) Selective pattern of motor system damage in gamma-synuclein transgenic mice mirrors the respective pathology in amyotrophic lateral sclerosis. Neurobiology of Disease, 48(1), 124-131.
Bachurin SO, Shelkovnikova TA, Ustyugov AA, Peters O, Khritankova I, Afanasieva MA, Tarasova TV, Alentov II, Buchman VL & Ninkina NN (2012) Dimebon Slows Progression of Proteinopathy in γ-Synuclein Transgenic Mice. Neurotoxicity Research, 22(1), 33-42.
Shelkovnikova TA, Kulikova AA, Tsvetkov FO, Peters O, Bachurin SO, Bukhman VL & Ninkina NN (2012) [Proteinopathies--forms of neurodegenerative disorders with protein aggregation-based pathology].. Mol Biol (Mosk), 46(3), 402-415.
Kokhan VS, Van’kin GI, Ninkina NN, Shelkovnikova TA & Bachurin SO (2011) Impaired spatial and working memory in ageing mice with targeted inactivation of α-synuclein gene. Doklady Biological Sciences, 441(1), 354-356.
Shelkovnikova TA, Ustyugov AA, Millership S, Peters O, Anichtchik O, Spillantini MG, Buchman VL, Bachurin SO & Ninkina NN (2011) Dimebon Does Not Ameliorate Pathological Changes Caused by Expression of Truncated (1–120) Human Alpha-Synuclein in Dopaminergic Neurons of Transgenic Mice. Neurodegenerative Diseases, 8(6), 430-437.
Bachurin SO, Ustyugov AA, Peters O, Shelkovnikova TA, Buchman VL & Ninkina NN (2009) Hindering of proteinopathy-induced neurodegeneration as a new mechanism of action for neuroprotectors and cognition enhancing compounds. Doklady Biochemistry and Biophysics, 428(1), 235-238.
An H, Elvers KT, Gillespie JA, Jones K, Atack JR, Grubisha O & Shelkovnikova TA () A toolkit for the identification of NEAT1_2/paraspeckle modulators. Nucleic Acids Research.
An H & Shelkovnikova TA () Stress granules regulate paraspeckles: RNP granule continuum at work. Cell Stress, 3(12), 385-387.
Park S, Park S-K, Watanabe N, Hashimoto T, Iwatsubo T, Shelkovnikova TA & Liebman SW () Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies. PLOS Genetics, 15(8), e1008308-e1008308.
Van De Pette M, Tunster SJ, McNamara GI, Shelkovnikova T, Millership S, Benson L, Peirson S, Christian M, Vidal-Puig A & John RM () Cdkn1c Boosts the Development of Brown Adipose Tissue in a Murine Model of Silver Russell Syndrome. PLOS Genetics, 12(3), e1005916-e1005916.

Preprints

Kukharsky MS, Ninkina NN, An H, Telezhkin V, Wei W, de Meritens CR, Cooper-Knock J, Nakagawa S, Hirose T, Buchman VL & Shelkovnikova TA () Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice, Cold Spring Harbor Laboratory.

Research group

Wan-Ping Huang (PDRA)

Rachel Hodgston (PDRA)

Zhaklin Chalakova (research assistant)

Vedanth Kumar (technician)

Jessica Rayment (technician)

Brittany Ellis (PhD student)

Teaching interests

I am the lead on Phase 2A Research Attachment SSC for the Department of Neuroscience.

My lab also hosts postgraduate (MSc, Neuroscience, Oncology & Metabolism, visiting) students.

Professional activities and memberships

Regularly solicited to review grant applications and manuscripts.
Grants: MND Association; MRC; BBSRC; Strasbourg Institute for Advanced Studies (USIAS); Worldwide Cancer Research; French National Research Agency (ANR); Research Foundation Flanders’ (FWO); Israel Science Foundation; French Research Association on ALS; European Science Foundation.
Manuscripts: reviewed for >30 journals, including Nat Neurosci, Nat Commun; Trends Genet; J Cell Biol, EMBO Rep, Cell Rep. >40 papers, for full list– see Publons.
Acted as external PhD examiner for students at the University College London / Crick Institute and King’s College London.
Invited to speak at multiple departmental seminars (including UCL, universities in Australia, Japan, Italy, Russia) and conferences.
Participated in outreach events and patient-oriented activities, including demonstration at science festivals and MND guest research blog writing.

Current Projects

Regulation of RNP granules paraspeckles and stress granules under acute and chronic stress and in disease states (cellular models) - funded by the MND Association and BBSRC.
Mechanistic studies of the RNA-binding proteins FUS and TDP-43 in ALS and FTD – funded by MRC.
Therapeutic targeting of RNA and RNA-protein complexes (assay development and screening activities) – funded UKRI FLF and MRC.
Targeting axonal dysfunction in ALS by small molecule splicing correction – funded by MND Scotland.

The Medical School

Dr Tatyana Shelkovnikova

Journal articles

Preprints

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