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VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death

Nature Genetics volume 34, pages 383–394 (2003)Cite this article

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfaδ/δ mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes −2,578A/−1,154A/−634G or −2,578A/−1,154G/−634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1G93A mice crossbred with Vegfaδ/δ mice died earlier due to more severe motoneuron degeneration. Vegfaδ/δ mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.

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Figure 1: Genetic association of VEGF with ALS.
Figure 2: Role and therapeutic potential of VEGF in stimulating motoneuron survival.

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Acknowledgements

The authors thank A. Claeys and B. VanKeirsbilck for technical support, G. Breier for plasmids, the VIB Genetic Service Facility for pyrosequencing, B. Dermaut and C. van Duijn for critical discussions of the statistical analyses and K. Brepoels, A. Bouché, M. Demol, E. Gils, B. Hermans, S. Janssen, W. Man, A. Manderveld, K. Maris, W. Martens, C. Nijs, M. Nijs, S. Meynen, P. Van Wesemael, A. Van den Hoeck, B. Vanwetswinkel and S. Wyns for assistance. D.L. is supported by the Flemish Institute for the promotion of scientific research and E.S. by the Fund for Scientific Research, Belgium. This work is supported by grants from the Fund for Scientific Research, the Concerted Research Actions, Belgium and the European Union to P.C.; from the Scientific Projects Committee University of Birmingham to K.M.; from the Fund for Scientific Research and the Interuniversity Attraction Pole program to C.V.B. and W.R.; from Saitama Medical School Research Center and Maruki Memorial Special Scholarship to T.A.; and from the Nutrition and Toxicology and Growth and Development Research Institutes in Maastricht to R.V.

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Authors and Affiliations

  1. Flanders Interuniversity Institute for Biotechnology and Departments of Neurology and Internal Medicine, The Center for Transgene Technology and Gene Therapy, University Hospital Gasthuisberg, KU Leuven, B-3000, Leuven, Belgium

    Diether Lambrechts, Erik Storkebaum, Masafumi Morimoto, Frederik Desmet, Sabine Wyns, Vincent Thijs, Severine Vermeire, Paul Rutgeerts, Mieke Dewerchin, Lieve Moons, Robert Vlietinck, Wim Robberecht, Désiré Collen & Peter Carmeliet

  2. Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, B-2610, Belgium

    Jurgen Del-Favero & Christine Van Broeckhoven

  3. Department of Neurology, Umea University Hospital, and Institute of Clinical Neuroscience and Medical Genetics, Umea University, Umeå, S-901 85, Sweden

    Stefan L Marklund, Jörgen Andersson, Lars Beckman & Peter M Andersen

  4. Department of Neurology, The Medical School, University of Birmingham, Edgbaston, B15 2TT, UK

    Ingrid van Marion, Rhiannon Musson, Hardev Singh Pall & Karen E Morrison

  5. Departments of Neurology and Medical and Molecular Genetics, Guy's, King's and St. Thomas' School of Medicine and Institute of Psychiatry, King's College London, London, SE5 8AF, UK

    Ammar Al-Chalabi, Valerie Hansen, Nigel Leigh & Christopher Shaw

  6. INSERM 397, Endocrinologie et Communication Cellulaire, Institut Fédératif de Recherche Louis Bugnard, CHU Rangueil, Toulouse, 31403 CEDEX 4, France

    Stephanie Bornes & Hervé Prats

  7. Department of Clinical Sciences, Division of Psychiatry, Umea University, Umea, Sweden

    Rolf Adolfsson

  8. 4th Department of Medicine, Saitama Medical School, Moroyama, Iruma-gun, 350-0495, Saitama, Japan

    Shigehiro Katayama & Takuya Awata

  9. Service de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, Paris, 75015, France

    Loïc Lang-Lazdunski

  10. Department of Population Genetics, Genomics & Bioinformatics, University Maastricht, Maastricht, 6200 MD, The Netherlands

    Robert Vlietinck

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Correspondence to Peter Carmeliet.

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Lambrechts, D., Storkebaum, E., Morimoto, M. et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34, 383–394 (2003). https://doi.org/10.1038/ng1211

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