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
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology and Department of Neurology, University Hospital Gasthuisberg, KU Leuven, Leuven, B-3000, Belgium.
Nat Genet. 2003 Aug;34(4):383-94. doi: 10.1038/ng1211.
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.
肌萎缩侧索硬化症（ALS）是一种无法治愈的运动神经元退行性疾病。我们最近报道，Vegfa表达降低会导致Vegfa（delta/delta）小鼠出现类似ALS的运动神经元退化。在一项对来自瑞典的900多名个体以及来自比利时和英国的1000多名个体的荟萃分析中，我们现在报告，在VEGF启动子/前导序列中，单倍型-2,578A/-1,154A/-634G或-2,578A/-1,154G/-634G的纯合子个体患ALS的风险高1.8倍（P = 0.00004）。这些“风险”单倍型在体内降低了循环VEGF水平，并减少了VEGF基因转录、IRES介导的VEGF表达以及一种新型大VEGF异构体（L-VEGF）的体内翻译。此外，与Vegfa（delta/delta）小鼠杂交的SOD1（G93A）小鼠因更严重的运动神经元退化而死亡更早。Vegfa（delta/delta）小鼠在脊髓缺血后异常易患持续性麻痹，而用Vegfa治疗可保护小鼠免受缺血性运动神经元死亡。这些发现表明，VEGF是人类ALS中运动神经元退化的一个调节因子，并揭示了Vegfa对小鼠应激运动神经元的治疗潜力。
