. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron. 2013 May 8;78(3):440-55. PubMed.

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  1. This new study adds to the exciting and emerging field of non-ATG repeat-associated (RAN) translation. A number of neurodegenerative diseases are caused by expanded repeat sequences, making RAN translation of great interest. RAN translation was first shown to occur with expanded CAG repeats, which cause several neurodegenerative diseases including Huntington’s disease, and CTG repeats, which cause myotonic dystrophy and spinocerebellar ataxia type 8 (1). It was very recently shown that RAN translation also occurs with expanded GGGGCC repeats, which are a common cause of frontotemporal dementia and amyotrophic lateral sclerosis (2,3). Now Todd, Paulson, and colleagues show that CGG repeat expansions, which cause fragile X-associated tremor ataxia syndrome (FXTAS), also trigger RAN translation.

    This raises several important questions. Firstly, is RAN translation common to all the repeat expansion disorders? Secondly, as many of these diseases are characterized by aggregates of potentially toxic RNA, it will be essential to tease out the contribution of RNA and protein to neurodegeneration, as this will have important implications for developing appropriate therapies. Another key question is the mechanism by which RAN translation occurs. This study provides evidence that there may be different mechanisms causing RAN translation of different frames of the CGG repeat, adding a further layer of complexity. Finally, we now need to consider whether RAN translation has a physiological role and whether other non-repeat sequences could also trigger non-ATG translation, potentially opening up new areas of research.

    References:

    . Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):260-5. Epub 2010 Dec 20 PubMed.

    . Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013 Feb 20;77(4):639-46. PubMed.

    . The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013 Mar 15;339(6125):1335-8. Epub 2013 Feb 7 PubMed.