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Translational genetics: from Arabidopsis to Friedreich's ataxia

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posted on 27.02.2017, 02:39 authored by Tabib, Amanda Rose
Unstable tri-nucleotide microsatellite repeats are the causal mutation underlying more than 40 severe neuromuscular and neurodegenerative disorders in humans including Huntington’s disease, Fragile X syndrome, Myotonic dystrophy and Friedreich’s ataxia. These disorders are collectively referred to as tri-nucleotide repeat disorders (TNRD)s. To date there is currently no effective treatment for these disorders, which are mostly progressive, late-onset and ultimately fatal. The mechanisms contributing to these disorders are not fully known and this is largely due to a lack of suitable model systems. Recently, a type of TNRD was discovered in the Bur-0 strain of the model plant Arabidopsis thaliana. The Arabidopsis tri-nucleotide repeat (TNR) expansion defect is very similar at the basic molecular level to the human TNRD Friedreich’s ataxia (FRDA). Both are caused by dramatic intronic GAA/TTC trinucleotide repeat expansions that result in decreased expression of their affected genes, they both exhibit somatic variation and repeat instability to similar extents. Therefore in this thesis, I take advantage of the Bur-0 TNR expansion model to analyse similarities, define mechanisms and exploit them in a translational approach to identify potential target pathways and small molecules for treatment of FRDA. In this thesis I analyze the mutational dynamics of the TTC/GAA repeat tract in wild A. thaliana populations in Ireland (from where the original Bur-0 accession was collected) and recover wild accessions with the expanded mutant allele. The expanded allelic variant was found to be maintained in wild at a relatively high frequency. I also explore the population structure of the Irish accessions and show that the repeat expansion is present in more than one sub-population of Irish accessions. I then go on to show that certain characteristics known to occur in human disorders, such as ‘genetic anticipation’ and the involvement of DNA repair pathways, are also occurring in the Bur-0 model. I then take a translational approach from Arabidopsis to a human FRDA cell culture model. I exploit the discovery of a novel mechanism discovered in plants in our group, which showed that TTC/GAA repeat expansion can lead to an increase in smallRNAs mapping to genes that harbor them. Taking a translational approach I show that there is an increase in smallRNAs that map to the defective FXN locus. I demonstrate that blocking smallRNA pathways actually help to increase FXN expression in FRDA cells. Furthermore, I test additional compounds identified through a screen previously done in the lab on the Bur-0 plants and through this identify additional compounds that increase FXN expression. Thus these translational approaches have identified potential therapeutic drug candidates for FRDA and potentially other TNRDs. Overall, the work in this thesis explores the similarities and shows Bur-0 as a potential model for studying various aspects of TNRD research that can potentially be translatable to the human disorders.


Campus location


Principal supervisor

Sureshkumar Balasubramanian

Year of Award


Department, School or Centre

Biological Sciences


Doctor of Philosophy

Degree Type



Faculty of Science