Dr Guillaume Hautbergue FRSB PhD PGCertHE FHEA
Senior Lecturer in Translational RNA Biology
Head of the RNA Biology Laboratory
Department of Neuroscience
Sheffield Institute for Translational Neuroscience
University of Sheffield
385a Glossop Road
Tel: +44 (0)114 2222252
Administrator: Heather Cartledge
Tel: +44 (0)114 2222278
Senior Lecturer in Translational RNA Biology January 2019 - present
Lecturer in Translational Biology December 2012 - December 2018
Senior Experimental Officer March 2010 – November 2012
Post-Doctoral Research Associate January 2002 – February 2010
Ph.D. of Molecular and Cellular Biology (Very Best Commendation with Honour)
French National Service October 1996 – July 1997
Molecular and Cellular Biology Advanced Studies Diploma June 1996
M.Sc. Biochemistry (With Distinction) June 1995
Biochemistry Higher Technological Certificate (Best Commendation) June 1993
First National Prize in Biochemistry June 1990
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?
|Research Funding Sponsors||
Student awards: 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.
Research in the laboratory focuses on the mechanisms of neurodegeneration and the identification of therapeutic strategies of neuroprotection in Motor Neurone Disease (MND) also called Amyotrophic Lateral Sclerosis (ALS), Fragile X Tremor and Ataxia Syndrome (FXTAS), Spinal Muscular Atrophy (SMA), Parkinson’s disease (PD) and ageing of the brain. In particular, we aim to identify RNA changes that cause ALS and understand whether neurodegeneration linked to C9ORF72, SOD1 and TDP-43 variants involve converging mechanisms of altered RNA metabolism. We are also interested in investigating how these potentially relate to sporadic 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 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).
Using functional and structural studies, identify the molecular mechanisms driving the nuclear export and the repeat-associated non-AUG (RAN) translation of C9ORF72 repeat transcripts to design and test novel gene therapy approaches in patient-derived neurons/astrocytes, Drosophila, zebrafish and mouse models of diseases. This research led to a patent filed for the use of “Inhibitors of SRSF1 to treat neurological disorders” (PCT/GB2017/051539; International publication number WO2017207979A1). Similar studies are conducted for other microsatellite repeat expansion disorders including FXTAS.
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.
Functional analysis of the master energy homeostasis co-transcriptional activator PGC-1alpha in ageing and neurodegeneration.
Post-Doctoral Research Associates
Former PhD students for which I was the PI:
Undergraduate Research Technicians
Research Group Collaborators
Dr Guillaume Hautbergue has an excellent track record of publications. Over the past 18 years, he authored 42 original research articles including publications in high impact journals such as Science, Cell Press, Nature Publishing Group, EMBO J, PNAS, JACS, Brain and Acta Neuropathologica. He also authored 2 methodologies, 7 review articles, 1 editorial and 1 book chapter.
Allen SP, Hall B, Castelli LM, Francis L, Woof R, Siskos AP, Kouloura E, Gray E, Thompson AG, Talbot K, Higginbottom A, Myszczynska M, Allen CF, Stopford MJ, Hemingway J, Bauer CS, Webster CP, De Vos KJ, Turner MR, Keun HC, Hautbergue GM, Ferraiuolo L and Shaw PJ. Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis. Brain 2019; 142(3):586-605
Cooper-Knock J, Moll T, Ramesh T, Castelli L, Beer A, Robins H, Fox I, Niedermoser I, Van Damme P, Moisse M, Robberecht W, Hardiman O, Panades MP, Assialioui A, Mora JS, Nazli Basak A, Morrison KE, Shaw CE, Al-Chalabi A, Landers JE, Wyles M, Heath PR, Higginbottom A, Walsh T, Kazoka M, McDermott CJ, Hautbergue GM, Kirby and Shaw PJ. Mutations in the glycosyltransferase domain of GLT8D1 are associated with familial amyotrophic lateral sclerosis. Cell Rep. 2019; 26, 2298-306
Varcianna A, Myszczynska MA, Castelli LM, O'Neill B, Kim Y, Talbot J, Nyberg S, Nyamali I, Heath PR, Stopford MJ, Hautbergue GM and Ferraiuolo L. Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS. EBioMedicine 2019 pii: S2352-3964(18)30569-3
Shaw MP, Higginbottom A, McGown A, Castelli LM, James E, Hautbergue GM, Shaw PJ and Ramesh TM. Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features. Acta Neuropathol Commun. 2018; 6(1):125
Iannitti T, Scarrott J, Likhite S, Coldicott I, Lewis K, Heath P, Higginbottom A, Myszczynska M, Milo M, Hautbergue GM, Meyer K, Kaspar B, Ferraiulo L, Shaw PJ and Azzouz M. Translating SOD1 gene silencing towards the clinic: A highly efficacious, off-target free and biomarker-supported strategy for familial ALS. Mol. Ther. Nucleic Acids 2018; 12:75-88
Castelli LM, Lin YH, Ferraiuolo L, Sanchez-Martinez A, Ning, K, Azzouz M, Whitworth AJ, Shaw PJ and Hautbergue GM*. SRSF1-dependent nuclear export of C9ORF72 repeat-transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection. Invited Research Highlight review. Ther Targets Neurol Dis. 2018; 4:e1619 (*Corresponding author)
Cooper-Knock J, Robins H, Niedermoser I, Wyles M, Heath PR, Higginbottom A, Walsh T, Kazoka M; Project MinE ALS Sequencing Consortium, Ince PG, Hautbergue GM, McDermott CJ, Kirby J and Shaw PJ. Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype. Front Mol Neurosci. 2017; 10:370
Chandran JS, Sharp PS, Karyka E, Aves-Cruzeiro JMDC, Coldicott I, Castelli L, Hautbergue G, Collins MO and Azzouz M. Site Specific Modification of Adeno-Associated Virus Enables Both Fluorescent Imaging of Viral Particles and Characterization of the Capsid Interactome. Sci Rep. 2017; 7(1):14766
Rust A*, Partridge LJ, Davletov B and Hautbergue GM*. The Use of Plant-Derived Ribosome Inactivating Proteins in Immunotoxin Development: Past, Present and Future Generations. Invited review. Toxins (Basel) 2017; 9(11) pii: E344 (*Corresponding authors)
Walker C, Herranz-Martin S, Karyka E, Liao C, Lewis K, Elsayed W, Lukashchuk V, Chiang SC, Ray S, Mulcahy PJ, Jurga M, Tsagakis I, Iannitti T, Chandran J, Coldicott I, De Vos KJ, Hassan MK, Higginbottom A, Shaw PJ, Hautbergue GM*, Azzouz M and El-Khamisy SF. C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat Neurosci. 2017; 20(9):1225-35 (*PhD co-supervisor of first author C. Walker)
Hautbergue GM*,**, Castelli L*, Ferraiuolo L*, Sanchez-Martinez A, Cooper-Knock J, Higginbottom A, Lin YH, Bauer CS, Dodd JE, Myszczynska MA, Alam SM, Garneret P, Chandran JS, Karyka E, Stopford MJ, Smith EF, Kirby J, Meyer K, Kaspar BK, Isaacs AM, El-Khamisy SF, De Vos KJ, Ning K, Azzouz M, Whitworth AJ** and Shaw PJ. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nat Commun. 2017; 8:16063 (*Joint first authors, **Corresponding authors)
Webster CP, Smith EF, Bauer CS, Moller A, Hautbergue GM, Ferraiuolo L, Myszczynska MA, Higginbottom A, Walsh MJ, Whitworth AJ, Kaspar BK, Meyer K, Shaw PJ, Grierson AJ and De Vos KJ. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 2016; 35(15):1656-76
Hautbergue GM. Widespread RNA dysregulation in neurodegeneration: challenges and opportunities. Invited Editorial. Austin Neurol. 2016, 1(1):1002
Rust A, Hassan HHA, Sedelnikova S, Niranjan D, Hautbergue G, Abbas SA, Partridge L, Rice D, Binz T and Davletov B. Two complementary approaches for intracellular delivery of exogenous enzymes. Sci. Rep. 2015; 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. C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis. PLoS One 2015; 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. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. 2015; 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. Arginine methylation and citrullination of splicing factor proline- and glutamine-rich (SFPQ/PSF) regulates its association with mRNA. RNA 2015; 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*. Invited review: decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Invited Review. Neuropathol Appl Neurobiol. 2015; 41(2):109-34 (*Corresponding author) - Featured in 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. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 2014; 137(Pt7):2040-51
Tunnicliffe RB, Hautbergue GM, Wilson SA, Kalra P and Golovanov AP. Competitive and Cooperative Interactions Mediate RNA Transfer from Herpesvirus Saimiri ORF57 to the Mammalian Export Adaptor ALYREF. PLoS Pathog. 2014; 10:e1003907
Hautbergue GM*, Chang CT*, Walsh MJ, Viphakone N, van Dijk TB, Philipsen S and Wilson SA. Chtop is a component of the dynamic TREX mRNA export complex. EMBO J. 2013; 32:473-86 (*Joint first authors)
Viphakone N, Hautbergue GM, Walsh MJ, Chang C-T, Holland A, Folco EG, Reed R and Wilson SA. TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nature Commun. 2012; 3:1006
Knuckles P, Vogt MA, Lugert S, Milo M, Chong MM, Hautbergue GM, Wilson SA, Littman DR and Taylor V. Drosha regulates neurogenesis by controlling Neurogenin 2 expression independent of microRNAs. Nat. Neurosci. 2012; 15:962-9
Hautbergue GM*, Cruz-Migoni A*, Artymiuk PJ, Baker PJ, Bokori-Brown M, Chang CT, Dickman MJ, Essex-Lopresti A, Harding SV, Mahadi NM, Marshall LE, Mobbs GW, Mohamed R, Nathan S, Ngugi SA, Ong C, Ooi WF, Partridge LJ, Phillips HL, Raih MF, Ruzheinikov S, Sarkar-Tyson M, Sedelnikova SE, Smither SJ, Tan P, Titball RW, Wilson SA and Rice DW. A Burkholderia pseudomallei toxin inhibits helicase activity of translation factor eIF4A. Science 2011; 334:821-4 (*Joint first authors)
Tunnicliffe RB, Hautbergue GM, Kalra P, Jackson BR, Whitehouse A, Wilson SA and Golovanov AP. Structural basis for the recognition of cellular mRNA export factor REF by herpes viral proteins HSV-1 ICP27 and HVS ORF57. PLoS Pathog. 2011; 7(1):e1001244
Hautbergue GM, Hung ML, Walsh MJ, Snijders AP, Chang CT, Jones R, Ponting CP, Dickman MJ and Wilson SA. UIF, a New mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Curr Biol. 2009; 19:1918-24
Hautbergue GM*, Tintaru AM*, Hounslow AM, Hung ML, Lian LY, Craven CJ and Wilson SA. Structural and functional analysis of RNA and TAP binding to SF2/ASF. EMBO Rep. 2007; 8:756-62 (*Joint first authors)
Hautbergue GM*, Hargous Y*, Tintaru AM, Skrisovska L, Golovanov AP, Stevenin J, Lian LY, Wilson SA and Allain FH. Molecular basis of RNA recognition and TAP binding by the SR proteins SRp20 and 9G8. EMBO J. 2006; 25:5126-37 (*Joint first authors)
Hautbergue GM*, Golovanov AP*, Tintaru AM, Lian LY and Wilson SA. The solution structure of REF2-I reveals interdomain interactions and regions involved in binding mRNA export factors and RNA. RNA 2006; 12:1933-48 (*Joint first authors)