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Symmetric dimethylation of poly-GR correlates with disease duration in C9orf72 FTLD and ALS and reduces poly-GR phase separation and toxicity

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). Green open access

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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].

Type: Article
Title: Symmetric dimethylation of poly-GR correlates with disease duration in C9orf72 FTLD and ALS and reduces poly-GR phase separation and toxicity
Location: Germany
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s00401-019-02104-x
Publisher version: https://link.springer.com/article/10.1007/s00401-0...
Language: English
Additional information: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10088152
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