論文 - 詳細
| RRC ID | 1257 |
|---|---|
| 著者 | Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P. |
| タイトル | VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. |
| ジャーナル | Nat Genet |
| 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. |
| 巻・号 | 34(4) |
| ページ | 383-94 |
| 公開日 | 2003-8-1 |
| DOI | 10.1038/ng1211 |
| PII | ng1211 |
| PMID | 12847526 |
| MeSH | 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 |
| IF | 27.605 |
| 引用数 | 662 |
| WOS 分野 | GENETICS & HEREDITY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 29 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | GI-1(RCB0763) |