Gittings, LM;
Boeynaems, S;
Lightwood, D;
Clargo, A;
Topia, S;
Nakayama, L;
Troakes, C;
... Isaacs, AM; + view all
(2019)
Symmetric dimethylation of poly-GR correlates with disease duration in C9orf72 FTLD and ALS and reduces poly-GR phase separation and toxicity.
Acta Neuropathologica
10.1007/s00401-019-02104-x.
(In press).
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Abstract
A GGGGCC repeat expansion in C9orf72 is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Pathologically, patients are characterised by TDP-43 pathology and distinct inclusions containing dipeptide repeat proteins (DPRs) that are produced by repeat associated non-ATG initiated translation of the repeat expansion. This produces five different DPRs: poly-GA, poly-GR poly-PR poly-AP and poly-GP. Poly-GR and poly-PR have been shown to be highly toxic in in vitro and in vivo models, but the mechanisms are not entirely clear [1]. We investigated whether methylation of arginine residues in poly-GR (which is much more abundant than poly-PR) contributes to disease pathogenesis. Three types of arginine methylation can occur, monomethylarginine (MMA), or dimethylarginine in a symmetric (SDMA) or asymmetric (ADMA) confirmation. ADMA is the most prevalent modification with MMA and SDMA occurring at approximately 20–50% that of ADMA [2]. The importance of arginine methylation in FTD and ALS has recently come to light as methylation of arginine residues within the FTD/ALS-linked proteins FUS and hnRNPA2 is an important regulator of their liquid–liquid phase transition [7].
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