NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice.
Spaulding, Emily L
De Winter, Vicky
Burgess, Robert W
Oxford University Press (OUP)
MetadataShow full item record
Jennings, M. J., Kagiava, A., Vendredy, L., Spaulding, E. L., Stavrou, M., Hathazi, D., Grüneboom, A., et al. (2022). NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice.. Brain https://doi.org/10.1093/brain/awac055
Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. Here, we identify proteins in sera of patients and mouse models with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT. The severity of neuropathy in the patients was assessed by the CMT Neuropathy Examination Score (CMTES). We performed multitargeted proteomics on both sample sets to identify proteins elevated across multiple mouse models and CMT patients. Selected proteins and additional potential biomarkers, such as growth differentiation factor 15 (GDF15) and cell free mitochondrial DNA, were validated by ELISA and quantitative PCR, respectively. We propose that neural cell adhesion molecule 1 (NCAM1) is a candidate biomarker for CMT, as it was elevated in Gjb1-null, Hspb8K141N, GarsC201R and GarsP278KY mice as well as in patients with both demyelinating (CMT1A) and axonal (CMT2D, CMT2N) forms of CMT. We show that NCAM1 may reflect disease severity, demonstrated by a progressive increase in mouse models with time and a significant positive correlation with CMTES neuropathy severity in patients. The increase in NCAM1 may reflect muscle regeneration triggered by denervation, which could potentially track disease progression or the effect of treatments. We found that member proteins of the complement system were elevated in Gjb1-null and Hspb8K141N mouse models as well as in patients with both demyelinating and axonal CMT, indicating possible complement activation at the impaired nerve terminals. However, complement proteins did not correlate with the severity of neuropathy measured on the CMTES scale. Although the complement system does not seem to be a prognostic biomarker, we do show complement elevation to be a common disease feature of CMT, which may be of interest as a therapeutic target. We also identify serum GDF15 as a highly sensitive diagnostic biomarker, which was elevated in all CMT genotypes as well as in Hspb8K141N, Gjb1-null, GarsC201R and GarsP278KY mouse models. Although we cannot fully explain its origin, it may reflect increased stress response or metabolic disturbances in CMT. Further large and longitudinal patient studies should be performed to establish the value of these proteins as diagnostic and prognostic molecular biomarkers for CMT.
M.J.J. was supported by the Medical Research Council (MRC) (UK) DiMeN and Cambridge DTPs. R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the MRC (MR/N025431/1 and MR/V009346/1), the European Research Council (309548), the Newton Fund (UK/Turkey, MR/N027302/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279, the CIHR and the ERARE Programme. K.A.K. was funded by a Muscular Dystrophy Association (MDA) and Charcot-Marie-Tooth Association (CMTA) grant 603003, as well as by a CMT Research Foundation (CMTRF) grant. AR received funding from the European Regional Development Fund (ERDF) (NME-GPS). L.V. is supported by a PhD fellowship from the Research Fund - Flanders (FWO). V.T. is part of the µNEURO Research Centre of Excellence of the University of Antwerp. V.T.’s research is supported in part by the Research Fund - Flanders (FWO Grant G041416N), University of Antwerp (TOP-BOF Grant 38694), Muscular Dystrophy Association (MDA Grant 577497), Medical Foundation Queen Elisabeth (GSKE), Association Belge contre les Maladies Neuromusculaire (ABMM), and the EU Horizon 2020 program Solve-RD (Grant agreement 779257). E.L.S. was supported by the National Institutes of Health (F31 NS100328). R.W.B. is supported by the National Institutes of Health (R37 NS054154). C.H.B. is grateful to Genome Canada for financial support through the Genomics Technology Platform (GTP: 264PRO). C.H.B. is also grateful for support from the Segal McGill Chair in Molecular Oncology at McGill University (Montreal, Quebec, Canada), and for support from the Warren Y. Soper Charitable Trust and the Alvin Segal Family Foundation to the Jewish General Hospital (Montreal, Quebec, Canada). The study was also supported by the MegaGrant of the Ministry of Science and Higher Education of the Russian Federation (Agreement with Skolkovo Institute of Science and Technology, No. 075-10-2019-083).
Addenbrooke's Charitable Trust (ACT) (64/17 A)
Wellcome Trust (109915/A/15/Z)
MRC (via University of Sheffield) (Unknown)
Evelyn Trust (19/14)
Wellcome Trust (109915_A_15_Z)
National Institute for Health Research (IS-BRC-1215-20014)
Embargo Lift Date
External DOI: https://doi.org/10.1093/brain/awac055
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333875
All Rights Reserved
Licence URL: http://www.rioxx.net/licenses/all-rights-reserved