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