Methylation of C9orf72 expansion reduces RNA foci formation and dipeptide-repeat proteins expression in cells. (26th January 2016)

• Record Type: Journal Article
• Authors: Bauer, Peter O.
• Is Part Of: Neuroscience letters. Volume 612(2016)
• Page Start: 204
• Page End: 209
• Publication Date: 2016-01-26
• Subjects: FTD frontotemporal dementia -- ALS amyotrophic lateral sclerosis -- C9orf72 chromosome 9 open reading frame 72 -- c9FTD/ALS FTD/ALS caused by expansion in C9orf72 gene -- RAN translation repeat-associated non-ATG translation -- DPR dipeptide-repeat protein -- poly(GP) poly-glycine-proline -- MSD Meso Scale Discovery -- M plasmid with methylated (GGGGCC)66 repeat -- U plasmid with unmethylated (GGGGCC)66 repeat -- HEK293T cells human embryonic kidney cells -- PBS phosphate-buffered saline -- EDTA ethylenediaminetetraacetic acid -- PMSF phenylmethylsulfonyl fluoride -- TBS-T tris–buffered saline with Triton X-100 -- FISH fluorescence in situ hybridization -- DEPC diethylpyrocarbonate; C9orf72 -- Repeat expansion -- Epigenetics -- DNA methylation -- Frontotemporal dementia -- Amyotrophic lateral sclerosis; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2015.12.018
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Repeat methylation reduces molecular pathology in cellular model of c9FTD/ALS. Novel method for C9orf72 repeat methylation levels quantification. This technique could potentially be used in patients as a bio- and prognostic marker. Abstract: A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), together referred to as c9FTD/ALS. It has been suggested that a loss of C9orf72 protein expression, the formation of toxic RNA foci and dipeptide-repeat proteins contribute to C9orf72 -related diseases. Interestingly, it has been shown that trimethylation of histones and methylation of CpG islands near the repeat expansion may play a role in the pathogenesis c9FTD/ALS. Recently, methylation of expanded repeat itself has been reported. To further elucidate the mechanisms underlying these diseases, the influence of epigenetic modification in the repeat expansion on its pathogenic effect was assessed. Here, a reduced formation of toxic RNA foci and dipeptide-repeat proteins upon methylation of the GGGGCC repeat in a cellular model of c9FTD/ALS is shown. Additionally, a novel methylcytosine-capture DNA hybridization immunoassay for semi-quantitative detection of the repeat methylation levels is presented, potentially usable for methylation analysis in patients carrying C9orf72 repeat expansion carriers as a diagnostic tool. Presented results suggest that increased level of pathogenic GGGGCC expansion methylation may be sufficient to alleviate the molecular pathology of the C9orf72 -related diseases.