Dr Guillaume Hautbergue MSc PhD PGCertHE FHEA
Lecturer in Translational RNA Neurobiology
Head of the RNA Biology Laboratory
Department of Neuroscience
Sheffield Institute of Translational Neuroscience
University of Sheffield
385a Glossop Road
Tel: +44 (0)114 2222252
Faculty Lecturer in Translational Neuroscience December 2012 - present
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 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)
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.
Post-Doctoral Research Associates
Research Group Collaborators
Dr Guillaume Hautbergue has an excellent track record of publications. Over the past 15 years, he has authored 29 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.
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, De Vos KJ (2016) The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 35 (15):1656-76
Hautbergue GM (2016) Widespread RNA Dysregulation in Neurodegeneration: Challenges and Opportunities. Editorial. Austin Neurol. 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. 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