Journal
JOURNAL OF NEUROSCIENCE
Volume 27, Issue 30, Pages 7929-7938Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1877-07.2007
Keywords
AU-rich element; 3 '-untranslated region; RNA-binding proteins; posttranscriptional gene regulation; HuR translocation; motor neurons
Categories
Funding
- NCI NIH HHS [CA97247, P50 CA097247] Funding Source: Medline
- NINDS NIH HHS [NS42834, R01 NS036761, NS36761, R01 NS042834] Funding Source: Medline
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Vascular endothelial growth factor (VEGF) plays a neuroprotective role in mice harboring mutations of copper-zinc superoxide dismutase 1 (SOD 1) in familial amyotrophic lateral sclerosis (ALS). Conversely, the loss of VEGF expression through genetic depletion can give rise to a phenotype resembling ALS independent of SOD 1 mutations. Here, we observe a profound downregulation of VEGF mRNA expression in spinal cords of G93A SOD 1 mice that occurred early in the course of the disease. Using an in vitro culture model of glial cells expressing mutant SOD 1, we demonstrate destabilization and downregulation of VEGF RNA with concomitant loss of protein expression that correlates with level of transgene expression. Using a luciferase reporter assay, we show that this molecular effect is mediated through a portion of the VEGF 3'-untranslated region (UTR) that harbors a class II adenylate/uridylate-rich element. Other mutant forms of SOD 1 produced a similar negative effect on luciferase RNA and protein expression. Mobility shift assay with a VEGF 3'-UTR probe reveals an aberrantly migrating complex that contains mutant SOD I. We further show that the RNA stabilizing protein, HuR (human antigen R), is translocated from nucleus to cytoplasm in mutant SOD 1 cells in vitro and mouse motor neurons in vivo. In summary, our data suggest that mutant SOD 1 gains a novel function, possibly by altering the ribonucleoprotein complex with the VEGF 3'-UTR. We postulate that the resultant dysregulation of VEGF posttranscriptional processing critically reduces the level of this neuroprotective growth factor and accelerates the neurodegenerative process in ALS.
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