VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death

D Lambrechts, E Storkebaum, M Morimoto, J Del-Favero, F Desmet, S L Marklund, S Wyns, V Thijs, J Andersson, I van Marion, A Al-Chalabi, S Bornes, R Musson, V Hansen, L Beckman, R Adolfsson, H Singh Pall, H Prats, S Vermeire, P RutgeertsS Katayama, T Awata, N Leigh, L Lang-Lazdunski, M Dewerchin, C Shaw, L Moons, R Vlietinck, K E Morrison, W Robberecht, C Van Broeckhoven, D Collen, P M Andersen, P Carmeliet

Research output: Contribution to journalArticlepeer-review

777 Citations (Scopus)

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(partial derivative/partial derivative) 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(partial derivative/partial derivative) mice died earlier due to more severe motoneuron degeneration. Vegfa(partial derivative/partial derivative) 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.
Original languageEnglish
Pages (from-to)383 - 394
Number of pages12
JournalNature Genetics
Volume34
Issue number4
DOIs
Publication statusPublished - 1 Aug 2003

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