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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, Désiré; Andersen, Peter M; Carmeliet, Peter
- 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.
- Publication
Nature genetics, 2003, Vol 34, Issue 4, p383
- ISSN
1061-4036
- Publication type
Journal Article
- DOI
10.1038/ng1211