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Title: VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death
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, Desire
Andersen, Peter M
Carmeliet, Peter # ×
Issue Date: Aug-2003
Publisher: Nature America, Inc.
Series Title: Nature genetics vol:34 issue:4 pages:383-94
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.
URI: 
ISSN: 1061-4036
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group Experimental Neurology
Vesalius Research Centre (-)
Translational Research in GastroIntestinal Disorders
Clinical Genetics Section (-)
Molecular and Vascular Biology
Animal Physiology and Neurobiology Section - miscellaneous
Laboratory of Behavioral and Developmental Genetics
Laboratory for Neurobiology (Vesalius Research Center)
Laboratory of Translational Genetics (Vesalius Research Center) (+)
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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