Sheffield Institute for
Translational Neuroscience

Dr Guillaume Hautbergue MSc PhD

Lecturer in Translational Neuroscience

Head of RNA Biology Laboratory


Research Interests

Our research focuses on identifying pathophysiological consequences of widespread RNA dysregulation in neurodegeneration in order to design, develop and test novel strategies of neuroprotective therapies.

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?

Research funding sponsors: Medical Research Council (MRC), The Royal Society and the Moody Endowment Fund.

 

 

Teaching Interests

  • 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 Translational Neuroscience and Molecular Medicine students:

        - Module MED620: Introduction to RNA biology – gene expression in health
        - Module MED623: RNA dysregulation in Amyotrophic Lateral Sclerosis
        - 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 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 member, Ms Sreenidhi Athi, who was awarded a Gold CREST Award (CREativity in Science and Technology Award) at the Nuffield Celebration Event in 2014.

 

Current Projects

Research in the laboratory focuses on the mechanisms of neurodegeneration and the identification of potential neuroprotective strategies in Motor Neurone Disease (MND) also called Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Parkinson’s disease (PD) and ageing of the brain. In particular, we aim to understand whether MND/ALS-neurodegeneration linked to C9ORF72, SOD1 and TDP-43 variants involve converging mechanisms of altered RNA metabolism and to investigate whether these relate to sporadic MND/ALS.

We use a combination of molecular biology, biochemistry, cellular biology, structural/functional and OMICS analysis in association with the development of novel experimental methodologies to uncover molecular mechanisms of gene expression that potentially cause and 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 pluripotent stem cells (iPSCs) or 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 the world largest collection of brain biosamples (Sheffield Brain Tissue Bank).
  • Identification of transcriptomes and translatomes. Since up-regulation of mRNA expression levels in transcriptome studies do not necessarily correlate with increased protein levels, the identification of all mRNA molecules undergoing translation into proteins (translatome) should better reflects protein expression changes and altered biological processes. Current methodologies aimed at identifying translatomes, such as polysome profiling, ribosome profiling and ribosome affinity purification, do not allow measuring the rates of actively translated mRNAs between biosamples, essentially generating qualitative results. The use of sucrose gradients also limits the high-throughput capacity of some of these complex techniques that are only performed by a few research groups around the world. We aim at developing a simpler technology that will allow purification and next generation sequencing of mRNA molecules actively translated into proteins.
  • Molecular mechanisms of TDP-43 proteinopathy, which involves the nuclear loss and cytoplasmic accumulation/ aggregation of TDP-43 and forms the hallmark of MND/ALS.
  • Identification of molecular mechanisms driving pathophysiological changes in C9ORF72-linked MND/ALS both at the levels of RNA-induced toxicity and non-ATG mediated RAN translation of toxic dipeptide repeat proteins.
  • Functional analysis of the master energy homeostasis co-transcriptional activator PGC-1alpha in ageing and neurodegeneration.

Research Team

Post-Doctoral Research Associates

  • Dr Lydia Castelli
  • Dr Margarita Segovia Roldan

PhD candidates

  • Ms Jennifer Dodd
  • Mr Simeon Mihaylov
  • Ms Evangelia Karyka (Secondary supervisor; PI: Prof Mimoun Azzouz)
  • Mr Aleks Rust (Secondary supervisor; PI: Prof Bazbek Davletov)
  • Ms Shaymaa Abbas (Secondary supervisor; PI: Dr Lynda Partridge)
  • Mr Peiyuan Zheng (Secondary supervisor; PI: Dr Mark Dickman)

Masters students

  • Ms Jennifer Strong (MPhil, Secondary supervisor; PI: Prof Dame Pamela Shaw)
  • Mr Jorge Garcia Morato (MSc Translational Neuroscience)
  • Mr Luis Solabre Valois (MSc Translational Neuroscience)

ERASMUS student

  • Mr Pierre Garneret (joint degree in medicine and science, Université de Bourgogne, France)

Research group collaborators

  • Motor neurone disease and spinal muscular atrophy: Prof Dame Pamela Shaw, Prof Mimoun Azzouz, Dr Laura Ferraiuolo, Dr Johnathan Cooper-Knock, Dr Richard Mead, Dr Jon wood and Dr Kurt De Vos (SITraN, University of Sheffield); Prof Sherif El-Khamisy (Molecular Biology and Biotechnology, University of Sheffield); Dr Alexander Withworth (MRC Mitochondrial Biology Unit, University of Cambridge); Dr Frank Hirth (Institute of Psychiatry, Psychology and Neuroscience, King's College London).
  • Protein methylation and citrullination, mass spectrometry, quantitative proteomics: Dr Mark Dickman (Chemical and Biological Engineering, University of Sheffield).
  • Integration, computational and statistical analysis of large data: Prof Winston Hide (SITraN, University of Sheffield; Harvard School of Public Health) and Dr Marta Milo (Biomedical Science, University of Sheffield).
  • 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) and Dr Lynda Partridge (Molecular Biology and Biotechnology, University of Sheffield).
  • Parkinson’s disease: Prof Oliver Bandmann and Dr Heather Mortiboys (SITraN, University of Sheffield).
  • Ageing of the brain and neuropathology: Prof Steve Wharton and Prof Paul Ince (SITraN, University of Sheffield).

Publications

Dr Guillaume Hautbergue has an excellent track record of publications. Over the past 15 years, he has authored 28 peer-reviewed original research articles published in high-standard international journals such as Science, Nature and Cell Press, Proceedings of the National Academy of Sciences, EMBO Journal, PLoS Pathogens, Brain and Acta Neuropathologica. He has also authored 2 methodology and 5 review articles.

RustA, HassanHHA, SedelnikovaS, NiranjanD, HautbergueG, AbbasSA, PartridgeL, RiceD, BinzT and Davletov B. Two complementary approaches for intracellular delivery of exogenous enzymes. Sci. Rep. 5:12444

Cooper-Knock J, Bury JJ, Heath PR, Wyles M, Higginbottom A, Gelsthorpe C, Highley JR, Hautbergue G, Rattray M, Kirby J and Shaw PJ (2015) C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis. PLoS One 10 (5): e0127376

Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, Pickering-Brown S, Kirby J, Hautbergue GM and Shaw PJ (2015) Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. 130 (1): 63-75

Hautbergue GM*, Snijders AP*, Bloom A, Williamson JC, Minshull TC, Phillips HL, Mihaylov SR, Gjerde DT, Hornby DP, Wilson SA, Hurd PJ and Dickman MJ (2015) Arginine methylation and citrullination of splicing factor proline- and glutamine-rich (SFPQ/PSF) regulates its association with mRNA. RNA 21 (3): 347-59 (* Joint first authors)

Walsh MJ, Cooper-Knock J, Dodd JE, Stopford MJ, Mihaylov SR, Kirby J, Shaw PJ and Hautbergue GM* (2015) Invited review: decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Neuropathol Appl Neurobiol. 41 (2): 109-34 (* Corresponding author) - Featured by the journal issue’s Front Cover.

Cooper-Knock J, Walsh MJ, Higginbottom A, Robin Highley J, Dickman MJ, Edbauer D, Ince PG, Wharton SB, Wilson SA, Kirby J, Hautbergue GM and Shaw PJ (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137 (Pt7): 2040-51

Tunnicliffe RB, Hautbergue GM, Wilson SA, Kalra P and Golovanov AP (2014) Competitive and Cooperative Interactions Mediate RNA Transfer from Herpesvirus Saimiri ORF57 to the Mammalian Export Adaptor ALYREF. PLoS Pathog. 10: e1003907

Walsh MJ, Dodd JE and Hautbergue GM* (2013) Ribosome-Inactivating Proteins: Potent Poisons and Molecular Tools. Review. Virulence 4 (8): 774-84 (* Corresponding author)

Hautbergue GM*, Chang C-T*, Walsh MJ, Viphakone N, van Dijk TB, Philipsen S and Wilson SA (2013) Chtop is a component of the dynamic TREX mRNA export complex. EMBO J. 32: 473-86 (* Joint first authors)

Viphakone N, Hautbergue GM, Walsh MJ, Chang C-T, Holland A, Folco EG, Reed R and Wilson SA (2012) TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nature Commun. 3: 1006

Hautbergue GM* and Wilson SA (2012) BLF1, the first Burkholderia pseudomallei toxin, connects inhibition of host protein synthesis with melioidosis. Review. Biochem Soc Trans. 40: 842-5 (* Corresponding author)

Knuckles P, Vogt MA, Lugert S, Milo M, Chong MM, Hautbergue GM, Wilson SA, Littman DR and Taylor V (2012) Drosha regulates neurogenesis by controlling Neurogenin 2 expression independent of microRNAs. Nat. Neurosci. 15: 962-9

Hautbergue G (2012) [Characterisation of Burkholderia pseudomallei Lethal Factor 1 (BLF1). A breakthrough against melioidosis]. Review. French. Med Sci (Paris) 28: 262-4

Hautbergue GM*, Cruz-Migoni A*, Artymiuk PJ, Baker PJ, Bokori-Brown M, Chang C-T, Dickman MJ, Essex-Lopresti A, Harding SV, Mahadi NM, Marshall LE, Mobbs GW, Mohamed R, Nathan S, Ngugi SA, Ong C, Ooi W-F, Partridge LJ, Phillips HL, Firdaus Raih M, Ruzhenikov S, Sarkar-Tyson M, Sedelnikova SE, Smither SJ, Tan P, Titball RW, Wilson SA and Rice DW (2011) A Burkholderia pseudomallei toxin inhibits helicase activity of translation factor eIF4A. Science 334: 821-4(* Joint first authors)

Tunnicliffe RB, Hautbergue GM, Kalra P, Jackson BR, Whitehouse A, Wilson SA and Golovanov AP (2011) 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

Hung ML, Hautbergue GM, Snijders AP, Dickman MJ and Wilson SA (2010) Arginine methylation of REF/ALY promotes efficient handover of mRNA to TAP/NXF1. Nucleic Acids Res. 38 (10): 3351-61

Walsh MJ, Hautbergue GM and Wilson SA (2010) Structure and function of mRNA export adaptors. Review. Biochem Soc Trans. 38: 232-6

Hautbergue GM, Hung ML, Walsh MJ, Snijders AP, Chang C-T, Jones R, Ponting CP, Dickman MJ and Wilson SA (2009) UIF, a New mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Curr Biol.  19 (22): 1918-24

Hautbergue GM, Hung ML, Golovanov AP, Lian L-Y and Wilson SA (2008) Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP. Proc Natl Acad Sci USA 105 (13): 5154-9

Hautbergue GM and Golovanov AP (2008) Increasing the sensitivity of cryoprobe protein NMR experiments by using the sole low-conductivity arginine glutamate salt. J Magn Reson 191 (2): 335-9

Hautbergue GM*, Tintaru AM*, Hounslow AM, Hung ML, Lian L-Y, Craven CJ and Wilson SA (2007) Structural and functional analysis of RNA and TAP binding to SF2/ASF. EMBO Rep. 8 (8): 756-62 (* Joint first authors)

Hautbergue GM*, Hargous Y*, Tintaru AM, Skrisovska L, Golovanov AP, Stevenin J, Lian L-Y, Wilson SA and Allain FH (2006) Molecular basis of RNA recognition and TAP binding by the SR proteins SRp20 and 9G8. EMBO J.25 (21): 5126-37 (* Joint first authors)   

Hautbergue GM*, Golovanov AP*, Tintaru AM, Lian L-Y and Wilson SA (2006) The solution structure of REF2-I reveals interdomain interactions and regions involved in binding mRNA export factors and RNA. RNA 12 (11): 1933-48 (* Joint first authors)

Golovanov AP, Hautbergue GM, Wilson SA and Lian L-Y (2004) A simple method for improving protein solubility and long-term stability. J. Am. Chem. Soc. 126 (29): 8933-9

Hautbergue G and Goguel V (2001) Activation of the Cyclin-Dependent Kinase CTDK-I requires the heterodimerization of two unstable subunits. J. Biol. Chem. 276 (11): 8005-13

Hautbergue G and Goguel V (1999) The yeast C-type cyclin Ctk2p is phosphorylated and rapidly degraded by the ubiquitin-proteasome pathway. Mol. Cell. Biol. 19 (4): 2527-34

 

Professional Activities

  • Editorial board member of the Journal “RNA and disease”.
  • Reviewership:

            - (i) Journals: PLOS, Medicinal Research Review, Biomolecules.

            - (ii) Research grant applications: MRC, MRC Foundation (MRF), Action Medical Research.

  • Holder of SITraN radio-isotopic licences / Responsible for radioactive work in SITraN.

  • Member of the Biochemical Society.

Biography

December 2012 - present:   Faculty Lecturer in Translational Neuroscience   
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 such as ALS/MND and SMA in order to develop novel strategies of neuro-protective therapies.

March 2010 – November 2012:   Senior Experimental Officer
August – November 2012: (i) Department of Neuroscience, SITraN, University of Sheffield, U.K. 
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.

March 2010 – July 2012: (ii) Department of Molecular Biology and Biotechnology, University of Sheffield, U.K.       
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).

January 2002 – February 2010:   Post-Doctoral Research Associate
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.

August 1997 – September 2001:   Ph.D. of Molecular and Cellular Biology (Very Best Commendation with Honour)
Université Pierre et Marie Curie Paris VI, Paris, France. 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.

October 1996 – July 1997:   French National Service
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.

June 1996:   Molecular and Cellular Biology Advanced Studies Diploma                                                       
Université Pierre et Marie Curie Paris VI, Paris, France. Ranked in the top 3 for a Ph.D. fellowship.

June 1995:   M.Sc. Biochemistry (With Distinction)
Université Denis Diderot Paris VII, Paris, France.

June 1993:   Biochemistry Higher Technological Certificate (Best Commendation)                                    
Ecole Nationale de Chimie Physique Biologie (ENCPB), Paris, France.

June 1990:   First National Prize in Biochemistry
France and French Overseas Countries in the competitive examination "Concours Général"

June 1990:   Biochemistry Baccalauréat (Best Commendation)                                                                 
Lycée Pierre et Marie Curie, Sens, France.

 

Awards

  • 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 RNA UK 2012 conference (2012)
  • 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)

Contact Details

Department of Neuroscience
Sheffield Institute for Translational Neuroscience
University of Sheffield
Room B49
385a Glossop Road
Sheffield
S10 2HQ

T: +44 (0)114 222 2252
E: g.hautbergue@shef.ac.uk