Project Title: Elucidating the mechanisms underlying C9ORF72 mutation toxicity using Drosophila

Project supervisors: Dr Jon Wood (SITraN) and Dr Alex Whitworth (BMS & CDBG)

Application deadline: Friday 14 December 2012.

Project description:

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal disease caused by the rapid, progressive degeneration of motor neurons. There is currently no cure and only a poor understanding of the pathogenic mechanism(s). The expansion of an intronic GGGGCC repeat in C9ORF72 has recently been found to be the most common genetic cause of ALS/MND identified to date (DeJesus-Hernandez et al., 2011; Renton et al., 2011). It is likely that this repeat expansion is toxic either via haploinsufficieny (DeJesus-Hernandez et al., 2011), and/or via a toxic gain-of-function mechanism at the RNA level, potentially through sequestration of RNA-binding proteins.

The aim of this project is to generate and characterise a novel Drosophila model of ALS via transgenic expression of non-coding GGGGCC repeats. Drosophila offers a powerful genetic system to rapidly investigate molecular mechanisms of disease in a multi-cellular organism, and has provided important mechanistic insight into the pathogenesis of other repeat expansion disorders (de Haro et al., 2006; Jin et al., 2007; Sofola et al., 2007).

This project will generate transgenic lines expressing non-coding GGGGCC repeats and test hypothetical pathogenic mechanisms and genetic interaction with other ALS gene mutations analysed. Methods for high-throughput screening to identify novel genetic modifiers will also be developed. Finally, to relate these findings to disease pathogenesis, the expression and localisation of modifiers of toxicity identified will be analysed in patient tissues.

This project is available to start in Autumn 2013, and is open to UK and EU students. International students may also apply but the higher fee status will need to be covered by additional funds or competitive award of a fee waiver.

References:

• de Haro et al. (2006).
  MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1.
  Hum Mol Genet. 15:2138-45.
• DeJesus-Hernandez et al. (2011).
  Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.
  Neuron. 72:245-56.
• Jin et al. (2007).
  Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome.
  Neuron. 55:556-64.
• Renton et al. (2011).
  A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.
  Neuron. 72:257-68.
• Sofola et al. (2007).
  RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS.
  Neuron. 55:565-71.

Contact Details:

Dr Alex Whitworth

Web: http://www.shef.ac.uk/bms/research/whitworth

Email: a.whitworth@sheffield.ac.uk

Dr Jon Wood

Web: http://sitran.dept.shef.ac.uk/wood.html

Email: j.d.wood1@sheffield.ac.uk