Dr Tatyana Shelkovnikova
PhD
Neuroscience, School of Medicine and Population Health
UKRI Future Leaders Fellow (Senior Research Fellow)
+44 114 22 22245
Full contact details
Neuroscience, School of Medicine and Population Health
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
Sheffield
S10 2HQ
- Profile
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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
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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
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Journal articles
- C9orf72 poly-PR forms anisotropic condensates causative of nuclear TDP-43 pathology. iScience, 110937-110937.
- Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion. Cell Reports, 43(7), 114421-114421.
- The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function. Nature Communications, 14. View this article in WRRO
- The Batten disease protein CLN3 is important for stress granules dynamics and translational activity. Journal of Biological Chemistry, 104649-104649.
- Oligonucleotide-recognizing topoisomerase inhibitors (OTIs): precision gene editors for neurodegenerative diseases?. International Journal of Molecular Sciences, 23(19).
- Atypical TDP-43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP. Brain Pathology. View this article in WRRO
- 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.
- Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy. RNA Biology, 18(11), 1546-1554.
- Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice. Translational Psychiatry, 10(1).
- Frameshift peptides alter the properties of truncated FUS proteins in ALS-FUS. Molecular Brain, 13(1).
- Stress granules regulate stress-induced paraspeckle assembly. Journal of Cell Biology, 218(12), 4127-4140.
- Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis. Cell Reports, 29(13), 4496-4508.e4.
- 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
- NEAT1 and paraspeckles in neurodegenerative diseases: A missing lnc found?. Non-coding RNA Research, 3(4), 243-252.
- Protective paraspeckle hyper-assembly downstream of TDP-43 loss of function in amyotrophic lateral sclerosis. Molecular Neurodegeneration, 13(1). View this article in WRRO
- Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly. Cell Death & Disease, 8(5), e2788-e2788.
- Modulation of p-eIF2α cellular levels and stress granule assembly/disassembly by trehalose. Scientific Reports, 7(1).
- Toxic gain of function from mutant
FUS
protein is crucial to trigger cell autonomous motor neuron loss. The EMBO Journal, 35(10), 1077-1097.
- A novel resource for studying function and dysfunction of α-synuclein: mouse lines for modulation of endogenous Snca gene expression. Scientific Reports, 5(1).
- 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).
- Gamma‐synuclein pathology in amyotrophic lateral sclerosis. Annals of Clinical and Translational Neurology, 2(1), 29-37. View this article in WRRO
- 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.
- Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent and RNA-independent mechanisms. Human Molecular Genetics, 23(19), 5211-5226.
- Compromised paraspeckle formation as a pathogenic factor in FUSopathies. Human Molecular Genetics, 23(9), 2298-2312.
- Modelling FUSopathies: focus on protein aggregation. Biochemical Society Transactions, 41(6), 1613-1617.
- Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm. Cell Cycle, 12(19), 3383-3391.
- 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.
- Chronic Administration of Dimebon does not Ameliorate Amyloid-β Pathology in 5xFAD Transgenic Mice. Journal of Alzheimer's Disease, 36(3), 589-596.
- 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.
- Dimebon Slows Progression of Proteinopathy in γ-Synuclein Transgenic Mice. Neurotoxicity Research, 22(1), 33-42.
- [Proteinopathies--forms of neurodegenerative disorders with protein aggregation-based pathology].. Mol Biol (Mosk), 46(3), 402-415.
- Impaired spatial and working memory in ageing mice with targeted inactivation of α-synuclein gene. Doklady Biological Sciences, 441(1), 354-356.
- 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.
- 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.
- TDP-43 in nuclear condensates: where, how, and why. Biochemical Society Transactions.
- A toolkit for the identification of NEAT1_2/paraspeckle modulators. Nucleic Acids Research.
- Stress granules regulate paraspeckles: RNP granule continuum at work. Cell Stress, 3(12), 385-387.
- 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.
- Cdkn1c Boosts the Development of Brown Adipose Tissue in a Murine Model of Silver Russell Syndrome. PLOS Genetics, 12(3), e1005916-e1005916.
Chapters
- RNP granules in ALS and neurodegeneration: From multifunctional membraneless organelles to therapeutic opportunities, International Review of Neurobiology Elsevier
Preprints
- Deep learning modeling of rare noncoding genetic variants in human motor neurons definesCCDC146as a therapeutic target for ALS, Cold Spring Harbor Laboratory.
- C9orf72 poly-PR condensation induces nuclear TDP-43 pathology and is inhibited by RNA in an optogenetic cell model, Cold Spring Harbor Laboratory.
- Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice, Cold Spring Harbor Laboratory.
- C9orf72 poly-PR forms anisotropic condensates causative of nuclear TDP-43 pathology. iScience, 110937-110937.
- Research group
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- Wan-Ping Huang (PDRA)
- Rachel Hodgson (PDRA)
- Anna Avila Sanchez (PDRA)
- Brittany Ellis (PhD student)
- Ruaridh Lang (PhD student)
Collaborators
- Sheffield: G Hautbergue, S Allen, J Cooper-Knock, M Dickman, K De Vos.
- External: JR Atack (Cardiff University, UK), N Locker (Pirbright, UK), A Fox (UWA, Australia), T Hashimoto (Tokyo, Japan), S Sweeney (York, UK), E Makeyev (King’s College London, UK), B Bax (Cardiff University, UK), G Burley (Strathclyde, UK), D Bong (Ohio, US).
- Industrial: AstraZeneca (MRC/AZ Centre for Lead Discovery)
- Teaching interests
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I am the division lead on Phase 2A Research Attachment SSC (Neuroscience).
My lab also regularly hosts postgraduate (Master’s – Neuroscience and Oncology & Metabolism; visiting) and undergraduate (e.g. research attachment) students.
- Professional activities and memberships
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Speaker at multiple departmental seminars (including UCL, universities in Australia, Japan, Italy) and multiple international conferences. Most recent speaking engagements:
International Symposium on ALS/MND (December 2023, Basel, Switzerland)
RNA granules 2023 conference (October 2023, Surrey, UK)
1st ICGEB Conference on TDP-43 function and dysfunction in diseases (September 2023, Trieste, Italy)
Robert Packard Center for ALS research seminar (June 2023)
Regularly solicited to review grant applications and manuscripts.
Grants: >30 reviewed, for MRC, BBSRC, MND Association, Wellcome Trust, Paul G. Allen Frontiers Group, Academy of Medical Sciences, Templeton Foundation, USIAS, Worldwide Cancer Research, French National Research Agency, Research Foundation Flanders, Israel Science Foundation, European Science Foundation and others.
Manuscripts: >50 reviewed for >20 journals, including Nat Neurosci, Nat Commun; Sci Transl Med; Trends Genet; EMBO Rep; Ann Neurol; J Cell Biol; Cell Rep and others.
Conference organising:
- RNA granules 2023 (9-11 October 2023, Surrey, UK), programme committee (co-organizer)
- 1st International Paraspeckle Biology symposium (8 October 2023, Surrey, UK), main organizer
PhD examiner and advisory roles:
- Examiner external: 5 PhD students (UCL/Crick Institute, King’s College London); internal: 1 PhD student
- Advisor to 6 PhD students (3 internal and 3 external)
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 (including MRC/AZ CLD)
- Targeting axonal dysfunction in ALS by small molecule splicing correction – funded by MND Scotland.
- Crosstalk between RNA regulation and metabolic alterations in ALS – funded by MND Association.