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      Specific biomarkers for C9orf72 FTD/ALS could expedite the journey towards effective therapies

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          Abstract

          A hexanucleotide repeat expansion in the C9orf72 gene is a common genetic cause of ALS and FTD. The repeats are translated into five different dipeptide repeat proteins ( DPRs). In this issue, Lehmer et al (2017) demonstrate that one of these DPRs, poly( GP), can be measured in the CSF of individuals with C9orf72 mutations. In conjunction with the findings from another recent study (Gendron et al, 2017), these DPR biomarkers may prove to be extremely valuable in the quest for effective therapies for C9 FTD/ ALS.

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          Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD

          Abstract The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non‐conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain‐of‐function mechanism. Here, we established a poly‐GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly‐GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases. The poly‐GP levels in asymptomatic carriers were similar to symptomatic c9ALS/FTD cases. Poly‐GP levels were not correlated with disease onset, clinical scores, and CSF levels of neurofilaments as a marker for axonal damage. Poly‐GP determination in CSF revealed a C9orf72 mutation carrier in our cohort and may thus be used as a diagnostic marker in addition to genetic testing to screen patients. Presymptomatic expression of poly‐GP and likely other DPR species may contribute to disease onset and thus represents an alluring therapeutic target.
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            Author and article information

            Contributors
            a.isaacs@ucl.ac.uk
            Journal
            EMBO Mol Med
            EMBO Mol Med
            10.1002/(ISSN)1757-4684
            EMMM
            embomm
            EMBO Molecular Medicine
            John Wiley and Sons Inc. (Hoboken )
            1757-4676
            1757-4684
            22 May 2017
            July 2017
            : 9
            : 7 ( doiID: 10.1002/emmm.v9.7 )
            : 853-855
            Affiliations
            [ 1 ] Department of Neurodegenerative Disease UCL Institute of Neurology London UK
            [ 2 ] Department of Genetics, Evolution and Environment Institute of Healthy Ageing University College London London UK
            Article
            EMMM201707848
            10.15252/emmm.201707848
            5524429
            28533210
            © 2017 The Authors. Published under the terms of the CC BY 4.0 license

            This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

            Page count
            Figures: 1, Tables: 0, Pages: 3, Words: 1736
            Product
            Funding
            Funded by: H2020 | H2020 Priority Excellent Science | H2020 European Research Council (ERC)
            Award ID: 648716 – C9ND
            Funded by: Motor Neurone Disease Association (MNDA)
            Funded by: Wellcome Trust
            Award ID: 107196/Z/14/Z
            Funded by: Brain Research Trust
            Funded by: Alzheimer's Research UK
            Categories
            News & Views
            News & Views
            Custom metadata
            2.0
            emmm201707848
            July 2017
            Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:21.07.2017

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