Published in:
Open Access
01-12-2014 | Letter to the Editor
RETRACTED ARTICLE: A new inducible transgenic mouse model for C9orf72-associated GGGGCC repeat expansion supports a gain-of-function mechanism in C9orf72-associated ALS and FTD
Authors:
Renate K Hukema, Fréderike W Riemslagh, Shamiram Melhem, Herma C van der Linde, Lies-Anne WFM Severijnen, Dieter Edbauer, Alex Maas, Nicolas Charlet-Berguerand, Rob Willemsen, John C van Swieten
Published in:
Acta Neuropathologica Communications
|
Issue 1/2014
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Excerpt
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two neurodegenerative disorders that share clinical, genetic and pathological overlap. In 2011, a hexanucleotide repeat (GGGGCC) expansion in the ‘chromosome 9 open reading frame 72’ (C9orf72) gene was identified as a cause of FTD and ALS [
1,
2]. This mutation has proven to be the most common genetic defect in the neurodegenerative field, especially in FTD and ALS [
3]. Patients harboring the C9orf72 repeat expansion can develop FTD, ALS or both and are therefore associated with wide clinical diversity [
4]. There have been multiple hypotheses about the underlying mechanisms by which the repeat expansion leads to neuropathology, including loss-of-function caused by haploinsufficiency of the endogenous C9orf72 protein product or gain-of-function induced by either RNA or protein toxicity. Either free RNA molecules containing the repeat expansion or RNA foci that sequester proteins could be toxic for cells. Alternatively, a pathogenic mechanism has been proposed for the production of toxic dipeptide repeat proteins (DPR) by repeat-associated non-AUG translation (RAN) of the repeat [
5,
6]. Interestingly, to differentiate between repeat “RNA-only” and DPR protein toxicity fruit fly models carrying a range of pure and RNA-only repeats have been generated. These studies demonstrated that the major toxic species were the DPR proteins [
7]. …