Professor Guillaume Hautbergue

FRSB, PhD, PGCertHE, FHEA

Neuroscience, School of Medicine and Population Health

Professor of Translational RNA Biology

Head of the RNA Biology Laboratory

MBChB Research SSC Academic Lead for the Medical School

Founding Director of Crucible Therapeutics

Guillaume Hautbergue
Profile picture of Guillaume Hautbergue
g.hautbergue@sheffield.ac.uk
+44 114 222 2252
+44 114 222 2278 (Administrator: Heather Cartledge)

Full contact details

Professor Guillaume Hautbergue
Neuroscience, School of Medicine and Population Health
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
Sheffield
S10 2HQ
Profile

Professor of Translational RNA Biology: January 2023 - present

Senior Lecturer in Translational RNA Biology January 2019 -December 2022

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

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).

Qualifications

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 alterations of gene expression in neurodegeneration for the development of novel therapeutic strategies using viral and non-viral gene therapy approaches.

Widespread dysregulation of the RNA metabolism has been recognised as a key pathological component causing multiple neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS), also known as motor neurone disease (MND, spinal muscular atrophy (SMA), Huntington’s disease (HD) and spinocerebellar ataxias (SCAs). Widespread alterations of transcriptomes have also been reported during physiological ageing of the brain while many neurodegenerative disorders are progressive late adult-onset diseases.

Although some genetic causes of often-fatal neurodegenerative 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 post-mortem brains extensively described large alterations of transcriptomes at all levels of the RNA metabolism including RNA biogenesis and processing, axonal transport and translation. Thousands of changes were reported in multiple cellular pathways with dysregulation reaching up to one third of the TDP-43 linked ALS transcriptomes. Since it is not feasible to separately investigate all individual changes, it remains challenging to distinguish alterations that are causing neurodegeneration from those which are consequences of initial RNA dysregulation – a bottleneck for the development of novel therapies.

In fact, the functional outcomes of widespread RNA dysregulation in neurodegeneration and ageing remain largely uncharacterised at the protein level, which is ultimately linked to neuronal 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 are synthesised from incorrectly processed RNAs? Roles of long intergenic non-coding (linc) RNAs that exhibit similar features to protein-coding genes?

Current Projects

Research in the laboratory currently focuses on the mechanisms of neurodegeneration and the identification of therapeutic strategies of neuroprotection in Amyotrophic Lateral Sclerosis (ALS) and Fragile X Tremor and Ataxia Syndrome (FXTAS). In particular, we aim to identify RNA changes that cause neurodegeneration and understand whether these involve converging mechanisms of altered RNA metabolism in different variants of diseases. We are also interested in investigating how these relate to sporadic ALS.

We use a combination of in vitro and in vivo models of diseases (mammalian cells, patient-derived neurons and astrocytes, Drosophila and mice) as well as molecular & cellular biology, biochemistry, structural/functional and OMICS investigations in association with the development of novel experimental methodologies to uncover molecular mechanisms of gene expression that cause and can rescue the neurodegeneration process.

  • Generation of non-neuronal and neuron-like inducible cell models of neurodegeneration to characterise early changes in gene expression and spread of dysregulation over time, in combination with studies in animal models and in astrocytes and motor neurons differentiated from induced neuronal progenitor cells (iNPCs) derived from patient fibroblasts. Whenever possible, we try validating our in vitro and in vivo results in human post mortem CNS tissues. We have access to one of the world largest collection of brain biosamples (Sheffield Brain Tissue Bank).
  • Functional and structural studies to identify the molecular mechanisms driving the nuclear export and the repeat-associated non-AUG (RAN) translation in C9ORF72-ALS/FTD and FXTAS
  • Molecular mechanisms of TDP-43 proteinopathy, which involves the nuclear loss and cytoplasmic aggregation of TDP-43.
  • Functional analysis of the master energy homeostasis co-transcriptional activator PGC-1alpha in neuronal ageing and models of senescence.
  • Genome-wide identification of transcriptomes and translatomes.
  • Founding Director of Crucible Therapeutics, a University of Sheffield biotech spinout company, developing novel therapeutic strategies of neuroprotection. Our technology involves granted patents and new applications for the use of gene therapy approaches in the potential treatment of neurodegenerative disorders - with a current focus on C9ORF72-ALS/FTD.
Publications

Journal articles

Conference proceedings papers

  • Cooper-Knock J, Moll T, Ramesh T, Castelli L, Shaw C, Al-Chalabi A, McDermott C, Hautbergue G & Shaw P (2019) 11.30 Mutations in the glycosyltransferase domain of GLT8D1 cause ALS. Journal of Neurology Neurosurgery & Psychiatry, Vol. 90(12) (pp e10) RIS download Bibtex download
  • Cooper-Knock J, Moll T, Ramesh T, Castelli L, Shaw C, Al-Chalabi A, McDermott C, Hautbergue G & Shaw P (2019) MUTATIONS IN THE GLYCOSYLTRANSFERASE DOMAIN OF GLT8D1 CAUSE ALS. JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol. 90(12) (pp E20-E21) RIS download Bibtex download
  • Alves-Cruzeiro JM, Karyka E, Bauer C, Coldicott I, Simon S, Hautbergue GM, Webster C, Myszczynska M, Higginbottom A, Ferraiuolo L & Azzouz M (2019) Gene editing as a potential therapeutic approach for ALS/FTD-associated with expanded C9ORF72. HUMAN GENE THERAPY, Vol. 30(8) (pp A22-A22) RIS download Bibtex download
  • Alves-Cruzeiro J, Karyka E, Bauer C, Coldicott I, Hautbergue G, Webster C, Castelli L, Simon S, Myszczynska M, Ferraiuolo L & Azzouz M (2019) AAV-mediated gene editing as a potential therapeutic approach for C9ORF72-linked ALS/FTD. HUMAN GENE THERAPY, Vol. 30(11) (pp A96-A96) RIS download Bibtex download
  • Allen SP, Hall B, Castelli L, Francis L, Woof R, Higginbottom A, Myszczynska M, Allen CF, Stopford MJ, Webster CP , De Vos K et al (2018) 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) RIS download Bibtex download
  • Tazzyman S, Hautbergue G, Khurram A, Bryan M, Chantry A & Fragiadaki M (2015) 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) RIS download Bibtex download

Datasets

Preprints

Research group
  • Dr Ya-Hui Lin (Post-doctoral Research Associate)
  • Dr Kamallia Mohd Imran (Post-doctoral Research Associate)
  • Dr Dave Burrows (Post-doctoral Research Associate)
  • Dr Monika Myszczynska (Post-doctoral Research Associate)
  • Dr Cleide Dos Santos Souza (Post-doctoral Research Associate)
  • Chloé Moutin (Research Technician)
  • Aytaç Gül (PhD student, primary supervisor)
  • Nikita Soni (PhD student, primary supervisor)
  • Sajid Shah (PhD student, primary supervisor)
  • Emma Bray (PhD student, primary supervisor)
  • Emily Tilley (PhD student, secondary supervisor)
  • Andreas Kosteletos (PhD student, secondary supervisor)
  • Duncan Garner (PhD student, secondary supervisor)
  • André Varcianna (PhD student, secondary supervisor)
  • Allan Shaw (PhD student, secondary supervisor)
  • Farah Mahiddine (PhD student, secondary supervisor)
  • Ouidad Khechaoui (PhD student, secondary supervisor)
Grants

Many thanks to the following funding bodies supporting our research:

  • Medical Research Council (MRC)
  • Biotechnology and Biological Sciences Research Council (BBSRC)
  • Engineering and Physical Sciences Research Council (EPSRC)
  • LifeArc
  • Motor Neurone Disease Association
  • The Royal Society
  • Alzheimer's Research UK                 
  • Industry: Takeda
Teaching activities
  • MBChB Research SSC Academic Lead for the Medical School (MED211)
  • MSc Advanced Cell and Gene Therapies course

            - Module Lead Principles of Gene and Cell therapies (NEU61008)

            - Module Lead Lab Research projects (MED625)

            - Academic Drug Discovery case study (NEU61009)

            - Journal club (NEU61011)

  • MSc in Translational Neuroscience and MSc in Translational Neuropathology courses:

- Introduction to RNA biology (MED620)
- RNA dysregulation in Amyotrophic Lateral Sclerosis (MED623)

- Introduction to translatomes (MED671)
- Laboratory research projects

  • 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 local primary and secondary schools and the public during Science week and Festival of the Mind and SITraN open days/symposium.
Professional activities and memberships
  • Invited and elected Fellow of the Royal Society of Biology (FRSB) in recognition of a prominent contribution to the advancement of the biological sciences (since 2019)
  • Member of the Biochemical Society (since 2013)
  • Editorial board member of the journal “RNA and Disease” (since 2014)
  • My Name’5 Doddie Foundation Grant Panel member (since 2023)
  • Member of the Department of Neuroscience Health and Safety Committee (since 2015)
  • Responsible and Holder of the Departmental licenses for radioactive work (since 2013)
  • PhD examination: (i) External examiner on 7 occasions (University College London, University of Oxford, King’s College London, Rhodes University in South Africa); (ii) Internal examiner on 6 occasions
  • Reviewing activities (since 2013): Grants: Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC), MND Association, Academy of Medical Sciences, MRC Foundation (MRF), European Research Council (ERC), French National Research Agency (ANR), French AFM Telethon, US National Science Foundation, Dutch ZonMw Vidi programs, Fondation Suisse de Recherche sur les Maladies Musculaires, Belgian Foundation against Cancer, etc.
  • Research articles and reviews: Nature, Nature Communications, Gene Therapy, Science Translational Medicine, Nucleic Acids Research, Neuron, EMBO J, Brain, Nature Methods, Nature Chemical Biology, Science Advances, Scientific Reports, etc.
  • Outreach activities in local schools and for public events in Sheffield (since 2013)
Research group collaborators
  • ALS and neurodegeneration: Prof Dame Pamela Shaw, Prof Mimoun Azzouz, Dr Richard Mead, Dr Tatyana Shelkovnikova, Dr Ryan West, Dr Suman De, Dr Johnathan Cooper-Knock, Prof Kurt De Vos and other colleagues (SITraN, University of Sheffield, UK); Dr Alexander Withworth (MRC Mitochondrial Biology Unit, University of Cambridge, UK); Prof Kung-Yao Chang (National Chung-Hsing University, Taiwan); Dr Adrian Isaacs (University College London Institute of Neurology, 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: Prof Mark Dickman (Chemical and Biological Engineering, University of Sheffield, UK)
  • Neuropathology, ageing and senescence: Prof Steve Wharton and Dr Robin Highley (SITraN, University of Sheffield); Prof Ilaria Bellantuono (Clinical Medicine, University of Sheffield, UK).
  • Parkinson’s disease: Prof Oliver Bandmann and Prof Heather Mortiboys (SITraN, University of Sheffield, UK)