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 Vegfaδ/δ 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, SOD1G93A mice crossbred with Vegfaδ/δ mice died earlier due to more severe motoneuron degeneration. Vegfaδ/δ 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.
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The authors thank A. Claeys and B. VanKeirsbilck for technical support, G. Breier for plasmids, the VIB Genetic Service Facility for pyrosequencing, B. Dermaut and C. van Duijn for critical discussions of the statistical analyses and K. Brepoels, A. Bouché, M. Demol, E. Gils, B. Hermans, S. Janssen, W. Man, A. Manderveld, K. Maris, W. Martens, C. Nijs, M. Nijs, S. Meynen, P. Van Wesemael, A. Van den Hoeck, B. Vanwetswinkel and S. Wyns for assistance. D.L. is supported by the Flemish Institute for the promotion of scientific research and E.S. by the Fund for Scientific Research, Belgium. This work is supported by grants from the Fund for Scientific Research, the Concerted Research Actions, Belgium and the European Union to P.C.; from the Scientific Projects Committee University of Birmingham to K.M.; from the Fund for Scientific Research and the Interuniversity Attraction Pole program to C.V.B. and W.R.; from Saitama Medical School Research Center and Maruki Memorial Special Scholarship to T.A.; and from the Nutrition and Toxicology and Growth and Development Research Institutes in Maastricht to R.V.
The authors declare no competing financial interests.
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Lambrechts, D., Storkebaum, E., Morimoto, M. et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34, 383–394 (2003). https://doi.org/10.1038/ng1211
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