RRC ID 1257
Author Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P.
Title VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.
Journal Nat Genet
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 Vegfa(delta/delta) 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(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) 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.
Volume 34(4)
Pages 383-94
Published 2003-8
DOI 10.1038/ng1211
PII ng1211
PMID 12847526
MeSH Aged Alleles Amyotrophic Lateral Sclerosis / drug therapy Amyotrophic Lateral Sclerosis / etiology Amyotrophic Lateral Sclerosis / genetics* Amyotrophic Lateral Sclerosis / pathology Animals Cell Death / drug effects Child Child, Preschool Endothelial Growth Factors / genetics* Endothelial Growth Factors / physiology Endothelial Growth Factors / therapeutic use Female Genetic Variation Haplotypes Humans Intercellular Signaling Peptides and Proteins / genetics* Intercellular Signaling Peptides and Proteins / physiology Intercellular Signaling Peptides and Proteins / therapeutic use Ischemia / pathology Lymphokines / genetics* Lymphokines / physiology Lymphokines / therapeutic use Male Mice Mice, Knockout Mice, Transgenic Middle Aged Motor Neurons / drug effects Motor Neurons / pathology Nerve Degeneration / genetics Paralysis / etiology Spinal Cord Ischemia / drug therapy Spinal Cord Ischemia / pathology Sweden Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
IF 25.455
Times Cited 662
WOS Category GENETICS & HEREDITY
Resource
Human and Animal Cells GI-1