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

Nat Genet. 2003 Aug;34(4):383-94. doi: 10.1038/ng1211.

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 types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Cell Death / drug effects
  • Child
  • Child, Preschool
  • Endothelial Growth Factors / genetics*
  • Endothelial Growth Factors / physiology
  • Endothelial Growth Factors / therapeutic use
  • Female
  • Genetic Variation
  • Haplotypes
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / physiology
  • Intercellular Signaling Peptides and Proteins / therapeutic use
  • Ischemia / pathology
  • Lymphokines / genetics*
  • Lymphokines / physiology
  • Lymphokines / therapeutic use
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Middle Aged
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • Nerve Degeneration / genetics
  • Paralysis / etiology
  • Spinal Cord Ischemia / drug therapy
  • Spinal Cord Ischemia / pathology
  • Sweden
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors