title: VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.
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.
authors.affiliation: The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology and Department of Neurology, University Hospital Gasthuisberg, KU Leuven, Leuven, B-3000, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Erik
authors.initials: E
authors.lastname: Storkebaum
authors.forename: Masafumi
authors.initials: M
authors.lastname: Morimoto
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.forename: Frederik
authors.initials: F
authors.lastname: Desmet
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Marklund
authors.forename: Sabine
authors.initials: S
authors.lastname: Wyns
authors.forename: Vincent
authors.initials: V
authors.lastname: Thijs
authors.forename: Jörgen
authors.initials: J
authors.lastname: Andersson
authors.forename: Ingrid
authors.initials: I
authors.lastname: van Marion
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bornes
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Musson
authors.forename: Valerie
authors.initials: V
authors.lastname: Hansen
authors.forename: Lars
authors.initials: L
authors.lastname: Beckman
authors.forename: Rolf
authors.initials: R
authors.lastname: Adolfsson
authors.forename: Hardev Singh
authors.initials: HS
authors.lastname: Pall
authors.forename: Hervé
authors.initials: H
authors.lastname: Prats
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Katayama
authors.forename: Takuya
authors.initials: T
authors.lastname: Awata
authors.forename: Nigel
authors.initials: N
authors.lastname: Leigh
authors.forename: Loïc
authors.initials: L
authors.lastname: Lang-Lazdunski
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Christopher
authors.initials: C
authors.lastname: Shaw
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Robert
authors.initials: R
authors.lastname: Vlietinck
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000368:Aged; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use; D007511:Ischemia / Q000473:pathology; D008222:Lymphokines / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics; D010243:Paralysis / Q000209:etiology; D020760:Spinal Cord Ischemia / Q000188:drug therapy / Q000473:pathology; D013548:Sweden; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors