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(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.
Lambrechts
Diether
D
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.
Storkebaum
Erik
E
Morimoto
Masafumi
M
Del-Favero
Jurgen
J
Desmet
Frederik
F
Marklund
Stefan L
SL
Wyns
Sabine
S
Thijs
Vincent
V
Andersson
Jörgen
J
van Marion
Ingrid
I
Al-Chalabi
Ammar
A
Bornes
Stephanie
S
Musson
Rhiannon
R
Hansen
Valerie
V
Beckman
Lars
L
Adolfsson
Rolf
R
Pall
Hardev Singh
HS
Prats
Hervé
H
Vermeire
Severine
S
Rutgeerts
Paul
P
Katayama
Shigehiro
S
Awata
Takuya
T
Leigh
Nigel
N
Lang-Lazdunski
Loïc
L
Dewerchin
Mieke
M
Shaw
Christopher
C
Moons
Lieve
L
Vlietinck
Robert
R
Morrison
Karen E
KE
Robberecht
Wim
W
Van Broeckhoven
Christine
C
Collen
Désiré
D
Andersen
Peter M
PM
Carmeliet
Peter
P
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
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors