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Posted in Journal Reviews on 23rd Jan 2015

A novel approach

Reviewer – Professor Kevin Talbot, Nuffield Department of Clinical Neurosciences, University of Oxford, UK

In the world of motor neurone disease the C9orf72 hexanucleotide (GGGGCC) expansion mutation remains the centre of attention. It is the commonest single genetic cause of neurodegeneration and serves as a common therapeutic target for up to 10% of all patients with amyotrophic lateral sclerosis and frontotemporal dementia. The potential to alter or block the expression of the aberrant RNA using oligonucleotides makes this the most therapeutically tractable target for ALS therapy. However, despite the intense pace of research in this area, the exact mechanism of toxicity is still unclear. Do RNA aggregates derived from the repeat expansion alter cellular homeostasis by binding to crucial ribonucleoproteins or is neurodegeneration driven by the novel mechanism of dipeptide protein toxicity from repeat associated non-ATG (RAN) translation highlighted in this section last year?1 A wonderfully elegant approach to answering this question has been recently published by Adrian Isaacs and colleagues at UCL, using the fruitfly eye as a model for toxicity. Taking advantage of the redundancy of the genetic code, they engineered flies in which the five different dipeptides that are predicted to be produced from different reading frames of the sense and antisense strands of the repeat RNA were produced in the absence of repeat RNA. The idea was to isolate protein from RNA toxicity. Similarly they produced repeat RNAs with stop-codons, every 12 GGGGCC repeats, to prevent expression of the dipeptides. The answer was striking. Two dipeptides (GR and PR), both containing arginine led to dramatic death of neurons in the fly eye, while expression of the interrupted, translation deficient, RNA alone did not cause cell death. A potential caveat is that RNA binding proteins are themselves arginine-rich and therefore toxicity from overexpression of arginine dipeptides in this system might be expected to disrupt critical cellular processes. Although this work does not immediately provide a conclusive mechanistic link between arginine dipeptides and ALS, it will serve as an important platform from which to explore the role of dipeptide repeat proteins in patients with ALS-FTD.
1 Update on the pathogenesis of ALS. Talbot K. ACNR. Volume 13, issue 6, p10.

Mizielinska S et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. SCIENCE. 2014 Sep 5;345(6201):1192-4.

ACNR 2015;14(6);19.  Online 23/01/15

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