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

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 Vegfa δ/δ mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium an...

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Bibliographic Details
Published in:	Nature genetics Vol. 34; no. 4; pp. 383 - 394
Main Authors:	Lambrechts, Diether, Storkebaum, Erik, Morimoto, Masafumi, Del-Favero, Jurgen, Desmet, Frederik, Marklund, Stefan L, Wyns, Sabine, Thijs, Vincent, Andersson, Jörgen, van Marion, Ingrid, Al-Chalabi, Ammar, Bornes, Stephanie, Musson, Rhiannon, Hansen, Valerie, Beckman, Lars, Adolfsson, Rolf, Pall, Hardev Singh, Prats, Hervé, Vermeire, Severine, Rutgeerts, Paul, Katayama, Shigehiro, Awata, Takuya, Leigh, Nigel, Lang-Lazdunski, Loïc, Dewerchin, Mieke, Shaw, Christopher, Moons, Lieve, Vlietinck, Robert, Morrison, Karen E, Robberecht, Wim, Van Broeckhoven, Christine, Collen, Désiré, Andersen, Peter M, Carmeliet, Peter
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.08.2003 Nature Publishing Group
Subjects:	Aged Agriculture Alleles Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - drug therapy Amyotrophic Lateral Sclerosis - etiology Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - pathology Animal Genetics and Genomics Animals Biological and medical sciences Biomedical and Life Sciences Biomedicine Cancer Research Cell Death - drug effects Cerebrospinal fluid. Meninges. Spinal cord Child Child, Preschool Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Diagnosis Embryology: invertebrates and vertebrates. Teratology Endothelial Growth Factors - genetics Endothelial Growth Factors - physiology Endothelial Growth Factors - therapeutic use Female Fundamental and applied biological sciences. Psychology Gene Function Genes Genetic aspects Genetic Variation Genetics Haplotypes Human Genetics Humans Hypoxia Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - physiology Intercellular Signaling Peptides and Proteins - therapeutic use Ischemia Ischemia - pathology Lymphokines - genetics Lymphokines - physiology Lymphokines - therapeutic use Male Medical sciences Mice Mice, Knockout Mice, Transgenic Middle Aged Molecular embryology Mortality Motor neurons Motor Neurons - drug effects Motor Neurons - pathology Mutation Nerve Degeneration - genetics Nervous system (semeiology, syndromes) Neurology Paralysis - etiology Pathogenesis Physiological aspects Risk factors Spinal cord Spinal Cord Ischemia - drug therapy Spinal Cord Ischemia - pathology Sweden Vascular endothelial growth factor Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Sweden United States England United Kingdom > UK Belgium Human Nervous system diseases Rodentia Cardiovascular disease Amyotrophic lateral sclerosis Motor neuron Vertebrata Mammalia Vascular endothelium growth factor Ischemia Mouse Central nervous system disease Death Degenerative disease Spinal cord disease
ISSN:	1061-4036, 1546-1718
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Summary:	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 Vegfa δ/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, SOD1 G93A mice crossbred with Vegfa δ/δ mice died earlier due to more severe motoneuron degeneration. Vegfa δ/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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ISSN:	1061-4036 1546-1718
DOI:	10.1038/ng1211