Symmetric dimethylation of poly-GR correlates with disease duration in C9orf72 FTLD and ALS and reduces poly-GR phase separation and toxicity
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 . 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 . 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 .
A previous report found no correlation of poly-GR with neurodegeneration or clinical phenotypes , while two more recent studies showed poly-GR inclusions did correlate with neurodegeneration [9, 10]. As these previous studies did not specifically label SDMA-GR, our findings provide new insights into the relationship of poly-GR inclusions with clinical phenotypes. Future studies are required to investigate why only SDMA-GR is associated with longer disease duration and age at death, and not ADMA-GR, as both forms were able to affect phase separation and toxicity (see Supplementary discussion, online resource for further discussion). In summary, our data show that arginine methylation is a common post-translation modification of poly-GR in C9orf72 patient brain that may influence disease course.
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