Dr Guillaume Hautbergue
FRSB, PhD, PGCertHE, FHEA
Department of Neuroscience
Senior Lecturer in Translational RNA Biology
Head of the RNA Biology Laboratory
+44 114 222 2252
Full contact details
Department of Neuroscience
385a Glossop Road
Senior Lecturer in Translational RNA Biology January 2019 - present
Lecturer in Translational Biology December 2012 - December 2018
Dr Hautbergue was recruited to the Sheffield Institute for Translational Neuroscience in August 2012 to set up the laboratory of RNA Molecular Biology, which is aimed at understanding the cause of gene expression dysregulation in neurodegenerative diseases, particularly focusing on ALS/MND, for the development of novel therapeutic strategies of neuroprotection.
Senior Experimental Officer March 2010 – November 2012
- Department of Neuroscience, SITraN, University of Sheffield, U.K. August – November 2012. Setting up the RNA biology laboratory and my research group in SITraN to apply my scientific skills in RNA biology research to the understanding of RNA processing dysregulation in ALS/MND. Department of Molecular Biology and Biotechnology, University of Sheffield, U.K. March 2010 – July 2012
- Structural and molecular mechanisms of human and viral mRNA nuclear export. Characterisation of ribonucleo-protein complexes. Expression, purification and solubility of proteins. Supervision of students/staff from other laboratories across Faculties. Module coordinator of undergraduate level 2 practical classes (MBB220, MBB226).
Post-Doctoral Research Associate January 2002 – February 2010
Department of Molecular Biology and Biotechnology, University of Sheffield, and Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, U.K.
Principal Investigator: Prof Stuart A. Wilson
The development of a general method to solubilise proteins led to the structure/function analysis of known and uncharacterised mRNA export adaptors establishing the presently accepted model for the molecular mechanisms of human mRNA nuclear export.
Ph.D. of Molecular and Cellular Biology (Very Best Commendation with Honour)
Université Pierre et Marie Curie Paris VI, Paris, France. August 1997 – September 2001
Department of Biochemistry and Molecular Genetics, Commissariat à l'Energie Atomique, Saclay, and Laboratory of Molecular Genetics, CNRS URA-1302, Ecole Normale Supérieure, Paris, France. Principal Investigator: Dr Valérie Goguel
Function of the yeast CTD Kinase I and atypical ubiquitin-mediated regulation of its activity.
French National Service October 1996 – July 1997
Sergeant (“Maréchal des Logis”) of the French Ground Armed Material Forces. Lead management training, First Help Training Certificate – Awarded a French National Defence bronze medal.
Molecular and Cellular Biology Advanced Studies Diploma June 1996
Université Pierre et Marie Curie Paris VI, Paris, France. Ranked in the top 3 for a Ph.D. fellowship.
M.Sc. Biochemistry (With Distinction) June 1995
Université Denis Diderot Paris VII, Paris, France.
Biochemistry Higher Technological Certificate (Best Commendation) June 1993
Ecole Nationale de Chimie Physique Biologie (ENCPB), Paris, France.
First National Prize in Biochemistry June 1990
France and French Overseas Countries in the competitive examination "Concours Général"
Biochemistry Baccalauréat (Best Commendation) June 1990
Lycée Pierre et Marie Curie, Sens, France
- Research interests
Our research focuses on identifying pathophysiological consequences of widespread RNA dysregulation in neurodegeneration in order to design, develop and test novel therapeutic strategies of neuroprotection using viral and non-viral gene therapy approaches.
Widespread dysregulation of the RNA metabolism has been recognised as a key pathophysiological component causing at least four neurodegenerative disorders: motor neurone disease (MND), also called Amyotrophic Lateral Sclerosis (ALS), spinal muscular atrophy (SMA), Huntington’s disease (HD) and spinocerebellar ataxias (SCAs).
Widespread alteration of the transcriptome has also been reported in normal ageing of the brain and many neurodegenerative disorders are late progressive adult-onset diseases. Neurodegeneration in Parkinson’s disease (PD) or Alzheimer’s disease (AD) is also likely to exhibit and/or involve broad alteration of the RNA metabolism and of multiple biological processes.
Although some genetic causes of these often-fatal diseases are known, the multifactorial molecular mechanisms governing pathogenesis and progression are still poorly understood. Genome-wide studies from cell or animal models and human brains extensively described large alterations of transcriptomes at all levels of the RNA metabolism including mRNA/miRNA biogenesis and processing, axonal transport and translation of mRNA.
Thousands of changes were reported in multiple cellular pathways with dysregulation reaching up to one third of the TDP-43 linked MND transcriptome. Since it is not feasible to investigate all individual changes, it is impossible to distinguish alterations that are causing neurodegeneration from those which are consequences of initial alterations – a bottleneck in the identification of gene expression-modifying therapies.
In fact, the functional outcomes of widespread RNA dysregulation in neurodegeneration and ageing remain uncharacterised at the protein levels, which are ultimately linked to neuron survival or death.
Beyond our investigation of altered RNA/protein expression levels and the development of neuroprotective strategies, we also aim at answering challenging scientific questions concerning RNA dysregulation in neurodegeneration and ageing: Proportion and identities of abnormally processed RNA molecules that escape the safeguarding mechanisms of nuclear retention?
Which abnormal proteins, sequences and numbers, get synthesised from incorrectly processed mRNAs? Roles of long intergenic non-coding (linc) RNAs that exhibit similar features to protein-coding genes?
- Therapeutic strategies for C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia. Current Opinion in Neurology.
- SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export : genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis. Molecular Neurodegeneration, 16(1).
- Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders. Biochemical Society Transactions.
- Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease. Aging Cell.
- The association between polygenic hazard scores and clinical markers of Alzheimer’s disease following stratification for APOE genotype. Alzheimer's & Dementia, 16(S4).
- The Association between Polygenic Hazard and Markers of Alzheimer’s Disease Following Stratification for APOE Genotype. Current Alzheimer Research, 17.
- Applications of machine learning to diagnosis and treatment of neurodegenerative diseases. Nature Reviews Neurology, 16, 440-456. View this article in WRRO
- Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis. Brain, 142(3), 586-605. View this article in WRRO
- TIGAR inclusion pathology is specific for Lewy body diseases. Brain Research, 1706, 218-223. View this article in WRRO
- Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis. Cell Reports, 26(9), 2298-2306.e5. View this article in WRRO
- Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS.. EBioMedicine, 40, 626-635. View this article in WRRO
- Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features. Acta Neuropathologica Communications, 6(1). View this article in WRRO
- Translating SOD1 Gene Silencing toward the Clinic: A Highly Efficacious, Off-Target-free, and Biomarker-Supported Strategy for fALS. Molecular Therapy : Nucleic Acids, 12, 75-88. View this article in WRRO
- Proteomic and cellular localisation studies suggest non-tight junction cytoplasmic and nuclear roles for occludin in astrocytes. European Journal of Neuroscience, 47(12), 1444-1456. View this article in WRRO
- Burkholderia Lethal Factor 1, a Novel Anti-Cancer Toxin, Demonstrates Selective Cytotoxicity in MYCN-Amplified Neuroblastoma Cells. Toxins, 10(7), 261-261. View this article in WRRO
- SRSF1-dependent nuclear export of C9ORF72 repeat transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection. Therapeutic Targets for Neurological Diseases, 4. View this article in WRRO
- Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype. Frontiers in Molecular Neuroscience, 10, 370-370. View this article in WRRO
- Site Specific Modification of Adeno-Associated Virus Enables Both Fluorescent Imaging of Viral Particles and Characterization of the Capsid Interactome. Scientific Reports, 7(1). View this article in WRRO
- RNA Nuclear Export: From Neurological Disorders to Cancer. Adv Exp Med Biol, 1007, 89-109. View this article in WRRO
- C9orf72 Expansion Disrupts ATM-mediated Chromosomal Break Repair. Nature Neuroscience, 20, 1225-1235. View this article in WRRO
- SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nature Communications, 8. View this article in WRRO
- C9ORF72 hexanucleotide repeat exerts toxicity in a stable, inducible motor neuronal cell model, which is rescued by partial depletion of Pten. Human Molecular Genetics, 26(6), 1133-1145. View this article in WRRO
- The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO Journal, 35(15), 1656-1676. View this article in WRRO
- View this article in WRRO Widespread RNA dysregulation in neurodegeneration: Challenges and Opportunities. Austin Neurology, 1(1).
- Two complementary approaches for intracellular delivery of exogenous enzymes. Scientific Reports, 5, 12444-12444. View this article in WRRO
- Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathologica, 130(1), 63-75. View this article in WRRO
- C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis. PLOS ONE, 10(5), e0127376-e0127376. View this article in WRRO
- The application of antibotoxsome, a novel cytotoxic conjugate, in cell death in in vitro models of pancreatic, liver, breast, cervical cancer, and myeloma.. Journal of Clinical Oncology, 33(15_suppl), e12018-e12018.
- Arginine methylation and citrullination of splicing factor proline- and glutamine-rich (SFPQ/PSF) regulates its association with mRNA. RNA, 21(3), 347-359. View this article in WRRO
- Invited Review: Decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Neuropathology and Applied Neurobiology, 41(2), 109-134. View this article in WRRO
- In C andida albicans hyphae, Sec2p is physically associated with SEC2 mRNA on secretory vesicles. Molecular Microbiology, 94(4), 828-842. View this article in WRRO
- Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions.. Brain, 137(Pt 7), 2040-2051. View this article in WRRO
- Competitive and Cooperative Interactions Mediate RNA Transfer from Herpesvirus Saimiri ORF57 to the Mammalian Export Adaptor ALYREF. PLoS Pathogens, 10(2). View this article in WRRO
- Ribosome-inactivating proteins: potent poisons and molecular tools.. Virulence, 4(8), 774-784.
- Chtop is a component of the dynamic TREX mRNA export complex.. EMBO J, 32(3), 473-486.
- Erratum: TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export.. Nat Commun, 4, 2377.
- TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export.. Nat Commun, 3, 1006. View this article in WRRO
- BLF1, the first Burkholderia pseudomallei toxin, connects inhibition of host protein synthesis with melioidosis.. Biochem Soc Trans, 40(4), 842-845.
- Drosha regulates neurogenesis by controlling neurogenin 2 expression independent of microRNAs.. Nat Neurosci, 15(7), 962-969.
- The structure and selectivity of the SR protein SRSF2 RRM domain with RNA.. Nucleic Acids Res, 40(7), 3232-3244. View this article in WRRO
- [Characterisation of Burkholderia pseudomallei Lethal Factor 1 (BLF1). A breakthrough against melioidosis].. Med Sci (Paris), 28(3), 262-264.
- A Burkholderia pseudomallei toxin inhibits helicase activity of translation factor eIF4A.. Science, 334(6057), 821-824. View this article in WRRO
- An interaction between KSHV ORF57 and UIF provides mRNA-adaptor redundancy in herpesvirus intronless mRNA export.. PLoS Pathog, 7(7), e1002138. View this article in WRRO
- FatJ acts via the Hippo mediator Yap1 to restrict the size of neural progenitor cell pools.. Development, 138(10), 1893-1902.
- Structural basis for the recognition of cellular mRNA export factor REF by herpes viral proteins HSV-1 ICP27 and HVS ORF57.. PLoS Pathog, 7(1), e1001244. View this article in WRRO
- The 1H, 13C and 15N backbone and side-chain assignment of the RRM domain of SC35, a regulator of pre-mRNA splicing.. Biomol NMR Assign, 5(1), 7-10.
- Arginine methylation of REF/ALY promotes efficient handover of mRNA to TAP/NXF1.. Nucleic Acids Res, 38(10), 3351-3361. View this article in WRRO
- Structure and function of mRNA export adaptors.. Biochem Soc Trans, 38(Pt 1), 232-236.
- The 1H, 13C and 15N backbone and side-chain assignment of the RRM domain of SC35, a regulator of pre-mRNA splicing. Biomolecular NMR Assignments, 1-4.
- UIF, a New mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA.. Curr Biol, 19(22), 1918-1924.
- Increasing the sensitivity of cryoprobe protein NMR experiments by using the sole low-conductivity arginine glutamate salt.. J Magn Reson, 191(2), 335-339.
- Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP.. Proc Natl Acad Sci U S A, 105(13), 5154-5159.
- Structural and functional analysis of RNA and TAP binding to SF2/ASF.. EMBO Rep, 8(8), 756-762.
- Assignment of 1H, 13C, and 15N resonances for SF2 RNA recognition motif 2.. J Biomol NMR, 38(2), 193.
- Molecular basis of RNA recognition and TAP binding by the SR proteins SRp20 and 9G8.. EMBO J, 25(21), 5126-5137.
- The solution structure of REF2-I reveals interdomain interactions and regions involved in binding mRNA export factors and RNA.. RNA, 12(11), 1933-1948.
- Assignment of 1H, 13C, and 15N resonances for the REF2-I mRNA export factor.. J Biomol NMR, 36 Suppl 1, 41.
- The prototype gamma-2 herpesvirus nucleocytoplasmic shuttling protein, ORF 57, transports viral RNA through the cellular mRNA export pathway.. Biochem J, 387(Pt 2), 295-308.
- A simple method for improving protein solubility and long-term stability.. J Am Chem Soc, 126(29), 8933-8939.
- CTD kinase I is involved in RNA polymerase I transcription.. Nucleic Acids Res, 32(19), 5851-5860.
- Activation of the cyclin-dependent kinase CTDK-I requires the heterodimerization of two unstable subunits.. J Biol Chem, 276(11), 8005-8013.
- The yeast C-type cyclin Ctk2p is phosphorylated and rapidly degraded by the ubiquitin-proteasome pathway.. Mol Cell Biol, 19(4), 2527-2534.
- A cell-penetrant peptide blocking C9ORF72-repeat RNA nuclear export suppresses neurodegeneration.
- The Use of Plant-Derived Ribosome Inactivating Proteins in Immunotoxin Development: Past, Present and Future Generations. Toxins, 9(11), 344-344. View this article in WRRO
- Ankhd1 enhances polycystic kidney disease development via promoting proliferation and fibrosis.
Conference proceedings papers
- 11.30 Mutations in the glycosyltransferase domain of GLT8D1 cause ALS. Journal of Neurology Neurosurgery & Psychiatry, Vol. 90(12) (pp e10)
- Inosine reverses motor neuron toxicity observed in amyotrophic lateral sclerosis patient astrocytes with an adenosine deaminase deficiency. Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol. 1859 (pp e23-e23)
- The application of antibotoxsome, a novel cytotoxic conjugate, in cell death in in vitro models of pancreatic, liver, breast, cervical cancer, and myeloma.. Journal of Clinical Oncology, Vol. 33(15)
- Research group
Post-Doctoral Research Associates
- Dr Lydia Castelli
- Dr Ya-Hui Lin
- Ms Charlotte Mason (PI)
- Ms Bridget Benson (PI)
- Mr Aytaç Gul (PI)
- Ms Monika Myszczynska (Secondary supervisor; PI: Dr Laura Ferraiuolo)
- Ms Emily Graves (Secondary supervisor; PI: Prof Mimoun Azzouz)
- Ms Amy Keerie (Secondary supervisor; PI: Dr Richard Mead)
- Mr Paolo Marchi (Secondary supervisor; PI: Prof Mimoun Azzouz)
Former PhD students for which I was the PI:
- Dr Jennifer Dodd (now at University of Liverpool)
- Dr Simeon R. Mihaylov (now at the Francis Crick Institute)
Undergraduate Research Technicians
- Ms Nikita Soni (2018-19)
- Mr Robin Pritchard (2016-17)
- Ms Amy Walton (2017-18).
Mr Theo Wing (MSc Translational Neuroscience student) was awarded the "Neuroscience Departmental Prize" for best lab project and presentation as well as "The Jody De Vos MND Research Award 2017" for best project in Motor Neurone Disease research.
Ms Michelle Vermeulen (MSc Translational Neuroscience student) shared the "Neuroscience Departmental Prize" for best lab project and presentation in 2018.
- Medical Research Council (MRC)
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Motor Neurone Disease Association
- Fondation Thierry Latran
- The Royal Society
- Teaching activities
MBChB Research SSC Academic Lead for the Medical School (March 2018 – present)
Innovation in Medical Education: development of a novel student-led approach, SACK (Student Assessment of Current Knowledge), to promote the active learning of undergraduates. Research projects are also available from a teacher perspective during the Student Selected Component of Phase 3A medical students. Please, contact Dr Guillaume Hautbergue if interested.
MSc in Translational Neuroscience, MSc in Genomic Medicine, MSc in Molecular Medicine:
- Module MED620: Introduction to RNA biology – gene expression in health
- Module MED623: RNA dysregulation in Amyotrophic Lateral Sclerosis
- Module MED670: Introduction to Human Genetics & Genomics
- Laboratory research projects
- 1-year research placement undergraduate students from Sheffield Hallam University
Laboratory projects concerning the molecular mechanisms of neurodegeneration in MND/ALS are available during the Student Selected Component of Phase 2A medical students.
Outreach engagement with the local Westbourne Junior School and Tapton Secondary School. Nuffield Research Placement laboratory projects are offered to selected Year-11 Tapton School students with support from the Nuffield Foundation and the Biology teacher Dr Nick Harris. Congratulations to our former members, Ms Nithya Rathi, Ms Sreenidhi Athi, Ms Nemah Mabger and Ms Khadija Kaabar, who were all awarded a Gold CREST Award (CREativity in Science and Technology Award) from the British Science Association.
Outreach activities with primary and secondary schools and the public during Science week and Festival of the Mind. Congratulations to our former members, Ms Nithya Rathi, Ms Sreenidhi Athi, Ms Nemah Mabger, Ms Khadija Kaabar, Ms Emma Bray, Ms Lucy Hanley and Mr Aria Izadi who were all awarded a Gold CREST Award (CREativity in Science and Technology Award) from the British Science Association. Emma Bray and Aria Izadi were also finalists of the National Big Bang UK Young Scientists and Engineers Fair.
- Outreach activities with primary and secondary schools, the public, patients and carers during Science week, Festival of the Mind and SITraN open days/symposium.
- Professional activities
- Editorial board member of the journal “RNA and Disease” (since 2014).
Member of the Departmental Strategic Vision and Appointment Committee (Since 2018)
Member of the Department of Neuroscience Learning and Teaching Committee (since 2018)
Department of Neuroscience Personal Academic Tutor Coordinator (since 2016)
Member of the Department of Neuroscience Health and Safety Committee (since 2015)
Academic representative of the Department of Neuroscience Reward and Recognition group (since 2015)
Academic representative of the Departmental of Neuroscience Outreach Committee that organizes public and school events (since 2014)
Responsible and Holder of the Departmental licenses for radioactive work (since 2013)
Invited Lecturer at the University of Oxford Autumn School in Neuroscience
PhD examination: (i) External examiner on 1 occasion; (ii) Internal examiner on 4 occasions
Outreach activities in local schools and for public events in Sheffield
Member of the Biochemical Society
Nucleic Acids Research, Nature, Nature Methods, Nature Chemical Biology, Scientific Reports, Acta Neuropathologica Communications, Human Molecular Genetics, PLOS journals, Toxins, The International Journal of Biochemistry and Cell Biology, Journal of Proteome Research, Medicinal Research Review, Biomolecules, etc.
Research grant applications
United Kingdom: Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC), MRC Foundation (MRF), Action Medical Research, Great Ormond Street Hospital, Leverhulme Trust, Association of British Neurologists for Clinical Research Training Fellowships
French AFM Telethon; Dutch ZonMw Vidi programs, Belgian Foundation against Cancer
- Selected member of the University of Sheffield Crucible (2012 - 2013), a competitive UK programme for improving communication, outreach activities and interdisciplinary collaborations
- Best seminar prize at the national RNA UK 2012 conference
- Research Associate Wellcome Trust VIP Award (2005/2006)
- French Ph.D. Fellowships: - "Fondation pour la Recherche Médicale" (October 2001 – December 2001) - "Association pour la Recherche sur le Cancer" (October 2000 – September 2001) - "Ministère de la Recherche et de l’Education Nationale" (October 1997 – September 2000)
- French National Defence bronze medal (1997)
- First National Prize in Biochemistry in the competitive examination "Concours Général" – France and French Overseas Countries (1990)
- Research group collaborators
- ALS and neurodegeneration: Prof Dame Pamela Shaw, Prof Mimoun Azzouz, Dr Laura Ferraiuolo, Dr Johnathan Cooper-Knock, Dr Tennore Ramesh, Dr Richard Mead and Dr Kurt De Vos (SITraN, University of Sheffield, UK); Dr Alexander Withworth (MRC Mitochondrial Biology Unit, University of Cambridge); Prof Kung-Yao Chang (National Chung-Hsing University, Taiwan); Prof David Lyons (Centre for Discovery Brain Sciences, University of Edinburgh, UK); Dr Yun-Ru (Ruby) Chen (Academia Sinica, Taiwan); Dr Adrian Isaacs (University College London Institute of Neurology, UK); Prof Sherif El-Khamisy (Molecular Biology and Biotechnology, University of Sheffield, UK).
- Structure determination of ribonucleoprotein complexes: Prof Frédéric HT Allain (Institute of Molecular Biology and Biophysics, ETH Zürich, Switzerland) and Dr Cyril Dominguez (Department of Molecular and Cell Biology, University of Leicester, UK)
- Protein methylation and citrullination, mass spectrometry, quantitative proteomics: Dr Mark Dickman (Chemical and Biological Engineering, University of Sheffield, UK).
- Integration, computational and statistical analysis of large data: Dr Marta Milo (Biomedical Science, University of Sheffield, UK), Dr Luisa Cutillo (School of Mathematics, University of Leeds, UK); Dr Mario R Guarracino (High Performance Computing and Networking Institute, Italy)
- Use of Ribosome-Inactivating Proteins (RIPs) as molecular tools and potential therapeutic vehicles/compounds for specific intra-neuronal delivery: Prof Bazbek Davletov (Biomedical Science, University of Sheffield, UK), Dr Lynda Partridge (Molecular Biology and Biotechnology, University of Sheffield, UK) and Prof Jim Deuchars (University of Leeds, UK).
- Parkinson’s disease: Prof Oliver Bandmann and Dr Heather Mortiboys (SITraN, University of Sheffield).
- Ageing of the brain and neuropathology: Prof Steve Wharton and Dr Robin Highley (SITraN, University of Sheffield).