Dr Olivier Becherel

Senior Research Officer

UQ Centre for Clinical Research
Faculty of Medicine
o.becherel@uq.edu.au
+61 7 334 66029

Overview

Currently, a Senior Research Officer at the UQ Centre for Clinical Research (UQCCR), I have demonstrated significant research achievements, commitment to scientific research excellence, post-graduate student supervision, and a strong potential for independent research leadership. My research activity has focused on the field of neurodegenerative disorders for the past 12 years, in particular in elucidating the molecular function of aprataxin and senataxin in the aetiology of human neurodegenerative syndromes ataxia oculomotor apraxia type 1 (AOA1) and type 2 (AOA2), respectively. Despite increasing knowledge of genetic mutations causing neurodegeneration, there is still an extremely limited understanding of the mechanisms that underlie pathogenesis. A better understanding of molecular changes involved is necessary to achieve the goal of effective therapy for patients. This research provides important addition to the knowledge base of disease onset and progression, and on mechanisms developed in neurons to protect against neurodegeneration. Identification of critical pathways related to disease processes has direct relevance to other more common neurodegenerative disorders.

Brief summary of the contributions I have made to the field of AOA2 research and the corresponding papers related to these findings for your reference.

  • First evidence for the role for senataxin in gene silencing via chromatin remodelling.

Senataxin controls meiotic silencing through ATR activation and chromatin remodelling.

Yeo AJ, Becherel OJ, Luff JE, Graham ME, Richard D, Lavin MF (2015) Cell Discovery 1, 15025; doi:1038/celldisc.2015.25.

  • Generated the first AOA2 induced pluripotent stem cell (iPSC) for the genetic disorder AOA2.

A new model to study neurodegeneration in ataxia oculomotor apraxia type 2.

Becherel OJ, Sun J, Yeo AJ, Nayler S, Fogel BL, Gao F, Coppola G, Criscuolo C, De Michele G, Wolvetang E, Lavin MF. Hum Mol Genet. 2015 Oct 15;24(20):5759-74.

  • Described a novel role for senataxin in the innate immune response.

Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis.

Miller MS, Rialdi A, Ho JS, Tilove M, Martinez-Gil L, Moshkina NP, Peralta Z, Noel J, Melegari C, Maestre AM, Mitsopoulos P, Madrenas J, Heinz S, Benner C, Young JA, Feagins AR, Basler CF, Fernandez-Sesma A, Becherel OJ, Lavin MF, van Bakel H, Marazzi I.Nat Immunol. 2015 May;16(5):485-94.

  • Identification of AOA2 and senataxin transcriptional gene signatures from patient cells.

Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2.

Fogel BL, Cho E, Wahnich A, Gao F, Becherel OJ, Wang X, Fike F, Chen L, Criscuolo C, De Michele G, Filla A, Collins A, Hahn AF, Gatti RA, Konopka G, Perlman S, Lavin MF, Geschwind DH, Coppola G. Hum Mol Genet. 2014 Sep 15;23(18):4758-69.

  • Demonstrated the in vivo resolution of DNA:RNA (R-loops) hybrids by senataxin and its role in fertility.

R-loops in proliferating cells but not in the brain: implications for AOA2 and other autosomal recessive ataxias.

Yeo AJ, Becherel OJ, Luff JE, Cullen JK, Wongsurawat T, Jenjaroenpun P, Kuznetsov VA, McKinnon PJ, Lavin MF. PLoS One. 2014 Mar 17;9(3):e90219. doi: 10.1371/journal.pone.0090219

  • Reported a key role for senataxin in spermatogenesis, meiosis and meiotic sex chromosome inactivation.

Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing.

Becherel OJ, Yeo AJ, Stellati A, Heng EY, Luff J, Suraweera AM, Woods R, Fleming J, Carrie D, McKinney K, Xu X, Deng C, Lavin MF. PLoS Genet. 2013 Apr;9(4):e1003435. doi: 10.1371/journal.pgen.1003435.

Senataxin protects the genome: Implications for neurodegeneration and other abnormalities.

Lavin MF, Yeo AJ, Becherel OJ. Rare Dis. 2013 Jun 6;1:e25230. doi: 10.4161/rdis.25230.

  • First demonstration for a role for senstaxin in RNA processing and gene regulation.

Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation.

Suraweera A, Lim Y, Woods R, Birrell GW, Nasim T, Becherel OJ, Lavin MF. Hum Mol Genet. 2009 Sep 15;18(18):3384-96.

  • A landmark report on the role of senataxin in the DNA damage response.

Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage.

Suraweera A, Becherel OJ, Chen P, Rundle N, Woods R, Nakamura J, Gatei M, Criscuolo C, Filla A, Chessa L, Fusser M, Epe B, Gueven N, Lavin MF. J Cell Biol. 2007 Jun 18;177(6):969-79.

  • Initial functional characterisation of aprataxin in the DNA damage response.

​Gueven N, Becherel OJ, Kijas AW, Chen P, Howe O, Rudolph JH, Gatti R, Date H, Onodera O, Taucher-Scholz G, Lavin MF (2004) Aprataxin, a novel protein that protects against genotoxic stress. Hum Mol Genet. 13:1081-93

Research Interests

  • Role of senataxin in protecting against neurodegeneration: Development and use of model systems
    Ataxia with oculomotor apraxia type 2 (AOA2) is a rare neurological disorder that was first described in 2000. The gene defective in AOA2 was identified as SETX coding for senataxin, a large DNA/RNA helicase that has been shown to function in RNA processing to protect the integrity of the genome. To date, only patient-derived lymphoblastoid cells, fibroblasts, and SETX knockdown cells have mostly been used to investigate AOA2, all of which are not the most suitable model to study the neurological phenotype. Recent disruption of the Setx gene in mice did not lead to neurobehavioral defects or neurodegeneration, making it difficult to study the etiology of AOA2. Thus, we have recently developed the first AOA2 neuronal model by reprogramming AOA2 patient fibroblasts using iPSC technology to study the role of senataxin in gene regulation and neurodegeneration in this syndrome.
  • Role of Senataxin gene expression regulation, neuroinflammation and neurodegeneration
    This project is designed to characterise a mouse model for the human genetic disorder Ataxia oculomotor apraxia type 2 (AOA2). The overall goal is to understand the in vivo role of senataxin, encoded by the SETX gene which is mutated in the human disorder AOA2. In particular, to study the role of senataxin in gene regulation and innate immunity in order to better understand the disease process and aetiology in AOA2.
  • Role of senataxin in RNA processing and gene regulation in meiosis
    To better understand the physiological role of senatxin, we disrupted the Setx gene mice, generating the first AOA2 mouse model. We demonstrated that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI). Furthermore, we showed that Setx-/- mice accumulate DNA:RNA hybrids (R-loops) in germ cells and proliferative tissues but not in post-mitotic neurons. In addition, we also uncovered a critical role for senataxin in ATR-related protein- and CHD4-mediated transcriptional silencing and chromatin remodeling during meiosis providing greater insight into its critical role in gene regulation to protect against neurodegeneration. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome.

Qualifications

  • Doctoral Degree, Louis Pasteur University

Publications

  • Yeo, Abrey J., Becherel, Olivier J., Luff, John E., Graham, Mark E., Richard, Derek and Lavin, Martin F. (2015) Senataxin controls meiotic silencing through ATR activation and chromatin remodeling. Cell Discovery, 1 15025: 1-20. doi:10.1038/celldisc.2015.25

  • Becherel, Olivier J., Sun, Jane, Yeo, Abrey J., Nayler, Sam, Fogel, Brent L., Gao, Fuying, Coppola, Giovanni, Criscuolo, Chiara, De Michele, Giuseppe, Wolvetang, Ernst and Lavin, Martin F. (2015) A new model to study neurodegeneration in ataxia oculomotor apraxia type 2. Human Molecular Genetics, 24 20: 5759-5774. doi:10.1093/hmg/ddv296

  • Miller, Matthew S., Rialdi, Alexamder, Ho, Jessica Sook Yuin, Tilove, Micah, Martinez-Gil, Luis, Moshkina, Natasha P., Peralta, Zuleyma, Noel, Justine, Melegari, Camilla, Maestre, Ana M., Mitsopoulos, Panagiotis, Madrenas, Joaquin, Heinz, Sven, Benner, Chris, Young, John A. T., Feagins, Alicia R., Basler, Christopher F., Fernandez-Sesma, Ana, Becherel, Olivier J., Lavin, Martin F., Van Bakel, Harm and Marazzi, Ivan (2015) Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis. Nature Immunology, 16 5: 485-494. doi:10.1038/ni.3132

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Publications

Journal Article

PhD and MPhil Supervision

Completed Supervision