Nature Genetics
34, 383 - 394 (2003)
Published online: 6 July 2003; | doi:10.1038/ng1211
VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic deathDiether Lambrechts1, Erik Storkebaum1, Masafumi Morimoto1, Jurgen Del-Favero2, Frederik Desmet1, Stefan L Marklund3, Sabine Wyns1, Vincent Thijs1, Jörgen Andersson3, Ingrid van Marion4, Ammar Al-Chalabi5, Stephanie Bornes6, Rhiannon Musson4, Valerie Hansen5, Lars Beckman3, Rolf Adolfsson7, Hardev Singh Pall4, Hervé Prats6, Severine Vermeire1, Paul Rutgeerts1, Shigehiro Katayama8, Takuya Awata8, Nigel Leigh5, Loïc Lang-Lazdunski9, Mieke Dewerchin1, Christopher Shaw5, Lieve Moons1, Robert Vlietinck1, 10, Karen E Morrison4, Wim Robberecht1, Christine Van Broeckhoven2, Désiré Collen1, Peter M Andersen3
& Peter Carmeliet11
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology and Departments of Neurology and Internal Medicine, University Hospital Gasthuisberg, KU Leuven, Leuven, B-3000, Belgium. 2
Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, B-2610 Antwerpen, Belgium. 3
Department of Neurology, Umea University Hospital, and Institute of Clinical Neuroscience and Medical Genetics, Umea University, S-901 85 Umeå, Sweden. 4
Department of Neurology, The Medical School, University of Birmingham, Edgbaston, B15 2TT, UK. 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. 6
INSERM 397, Endocrinologie et Communication Cellulaire, Institut Fédératif de Recherche Louis Bugnard, CHU Rangueil, 31403 Toulouse, CEDEX 4, France. 7
Department of Clinical Sciences, Division of Psychiatry, Umea University, Umea, Sweden. 8
4th Department of Medicine, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan. 9
Service de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, 75015 Paris, France. 10
Department of Population Genetics, Genomics & Bioinformatics, University Maastricht, 6200 MD Maastricht, The Netherlands.
Correspondence should be addressed to Peter Carmeliet peter.carmeliet@med.kuleuven.ac.beAmyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa
 / 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, SOD1
G93A mice crossbred with Vegfa
/ mice died earlier due to more severe motoneuron degeneration. Vegfa/ 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.
|
