NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice

Author:

Jennings Matthew J1ORCID,Kagiava Alexia2,Vendredy Leen3,Spaulding Emily L45,Stavrou Marina2ORCID,Hathazi Denisa1,Grüneboom Anika6,De Winter Vicky3,Gess Burkhard7,Schara Ulrike8,Pogoryelova Oksana9,Lochmüller Hanns101112,Borchers Christoph H131415ORCID,Roos Andreas1016,Burgess Robert W45,Timmerman Vincent3ORCID,Kleopa Kleopas A2ORCID,Horvath Rita1ORCID

Affiliation:

1. Department of Clinical Neurosciences, University of Cambridge , Cambridge , UK

2. Department of Neuroscience and Neuromuscular Disorders Centre, The Cyprus Institute of Neurology and Genetics , Nicosia , Cyprus

3. Peripheral Neuropathy Research Group, Department of Biomedical Sciences, Institute Born Bunge, University of Antwerp , Antwerp , Belgium

4. The Jackson Laboratory , Bar Harbor, ME , USA

5. Graduate School of Biomedical Sciences and Engineering, University of Maine , Orono, ME 04469 , USA

6. Leibniz-Institut für Analytische Wissenschaften—ISAS—e.V , Dortmund , Germany

7. Department of Neurology, University Hospital Aachen , Aachen , Germany

8. Centre for Neuromuscular Disorders in Children, University of Duisburg-Essen , Essen , Germany

9. Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals, NHS Foundation Trust , Newcastle upon Tyne , UK

10. Division of Neurology, Department of Medicine, The Ottawa Hospital, Brain and Mind Research Institute and Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa , Ottawa , Canada

11. Department of Neuropediatrics and Muscle Disorders, Medical Center–University of Freiburg, Faculty of Medicine , Freiburg , Germany

12. CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology , Barcelona , Spain

13. Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University , Montreal, Quebec , Canada

14. Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University , Montreal, Quebec , Canada

15. Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology , Moscow , Russia

16. Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum , Bochum , Germany

Abstract

Abstract 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.

Funder

Medical Research Council

Wellcome Trust Investigator

European Research Council

Newton Fund

Addenbrookes Charitable Trust

Evelyn Trust

Stoneygate Trust

Lily Foundation

International Centre for Genomic Medicine in Neuromuscular Diseases

NIHR Cambridge Biomedical Research Centre

Canadian Institutes of Health Research

Canadian Institutes of Health Research and Muscular Dystrophy Canada

Canada Foundation for Innovation

Muscular Dystrophy Association

Charcot-Marie-Tooth Association

CMT Research Foundation

European Regional Development Fund

University of Antwerp

Medical Foundation Queen Elisabeth

National Institutes of Health

Genomics Technology Platform

McGill University

Warren Y. Soper Charitable Trust

Alvin Segal Family Foundation

Ministry of Science and Higher Education of the Russian Federation

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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